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Mol Neurobiol
DOI 10.1007/s12035-015-9379-8
Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin
Ligase: Recent Unraveling of Neurobiological Mechanisms
Arun Upadhyay 1 & Ayeman Amanullah 1 & Deepak Chhangani 1 &
Ribhav Mishra 1 & Amit Prasad 2 & Amit Mishra 1
Received: 6 March 2015 / Accepted: 27 July 2015
# Springer Science+Business Media New York 2015
Abstract In healthy cell, inappropriate accumulation of poor
or damaged proteins is prevented by cellular quality control
system. Autophagy and ubiquitin proteasome system (UPS)
provides regular cytoprotection against proteotoxicity induced
by abnormal or disruptive proteins. E3 ubiquitin ligases are
crucial components in this defense mechanism. Mahogunin
Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the
Really Interesting New Gene (RING) finger family, plays a
pivotal role in many biological and cellular mechanisms.
Previous findings indicate that lack of functions of MGRN1
can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular
pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of
MGRN1; we also summarize possible beneficiary aspects of
this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological
mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets
for therapeutic intervention.
Keywords MGRN1 . Ubiquitin ligase . Cellular quality
control mechanism . Neurodegenerative diseases . Aging
* Amit Mishra
amit@iitj.ac.in
1
Cellular and Molecular Neurobiology Unit, Indian Institute of
Technology Jodhpur, Jodhpur, Rajasthan 342011, India
2
School of Basic Sciences, Indian Institute of Technology Mandi,
Mandi, Himachal Pradesh 175005, India
Introduction
Human cell normally contain billions of proteins, and normal
integral function of a protein is dependent on its shape, size,
and proper localization in appropriate cellular compartments
[1]. Proteins continuously perform all major work of cells, in
order to maintain cellular homeostasis. Millions of ribosomes
synthesize nascent polypeptide chains with an approximate
rate of six amino acids per second in cells [2, 3] (Fig. 1a).
Disruption in the confirmations of three-dimensional structure
of a polypeptide chains tends to misfold them, which may
result in abnormal toxic aggregation due to the failure of correct assembly or loss of protein control mechanism in cells [4].
Integrity of a newly synthesized protein is continually at risk
of abnormal folding and aggregation due to transcriptional
and/or translational failures or exposure of distinct stress conditions at both intracellular and extracellular levels Fig. 1b. To
survive under such non-tolerable stress conditions, cells
evolved a very efficient interconnected central surveillance
protein quality control mechanism that can either refold, degrade, and/or separate misfolded proteins with the help of
chaperones and two proteolytic systems [5].
Chaperones target hydrophobic stretches of unfolded proteins and also recognize misfolded proteins for their further
folding or degradation. Regular actions of chaperones are to
promote folding of newly synthesized proteins and to facilitate
their translocation across membranes to reduce the unwanted
load of aggregation [6]. Autophagy pathway is involved in the
degradation of major random cytoplasmic bulk of cell; recent
studies have elaborated the selective mechanism of autophagy
pathway with the help of chaperones and E3 ubiquitin ligases
in the clearance of non-native or poorly folded proteins [7]
Fig. 1c–e. Chaperone-assisted selective autophagy (CASA) is
an important mechanism, which helps in the muscle maintenance via degradation of damaged filamin [8]. Loss of CASA
Mol Neurobiol
Fig. 1 Illustrative representation of cellular protein quality control
mechanism. a In cells ribosomes translate mRNA into newly
synthesized chain of amino acids and molecular chaperones try to fold
them into a perfectly folded protein. b Exposure of different internal and
external cellular stress conditions contributes to influence misfolding and
aggregation in the crowded cellular milieu. c–e During stress conditions,
healthy cells limit accumulation of non-native proteins aggregation with
the help of cellular protein quality control mechanism (molecular
chaperones, various type of selective autophagy processes, ubiquitin
proteasome system, and lysosome system) and alleviate proteotoxic
insults in cells
functions leads to muscles weakness and declination of cytoskeleton architecture [9]. In living cells, isolation of misfolded
proteins, removal of unwanted aggregated proteins, and repair
of partially folded or non-native proteins improve interconnected networks of cellular cytoprotective mechanisms. In
the process of elimination of damaged proteins, chaperonemediated autophagy (CMA) is another very crucial and selective approach that takes help of lysosomes in the removal of
specific proteins [10]. To counter the challenges of protein
aggregation and solve the problem of misfolded proteins
clearance, cells evolved another alternative mechanism, i.e.,
chaperone-assisted proteasomal degradation (CAP) which
may increase cytoprotective potential of cells against toxic
proteins [11].
Here, we are representing a comprehensive overview of
this review article (see box). Our current review summarizes
the main framework for protein quality control mechanism
(QC) and then discusses various steps and components of
QC process. In next upcoming section, we narrow down our
focus on the linkage of less explored crucial E3 ubiquitin
ligase MGRN1 with ubiquitin system. We deliver welllinked information on molecular nature, gene structure, isoforms, mutations, and interacting proteins or crucial substrates
of MGRN1 E3 ubiquitin ligase with its roles in
Mol Neurobiol
pathobiological mechanisms. The next half of article comprehensively represents molecular functions of MGRN1 in neurodegeneration and then discusses the cellular defense role of
MGRN1 against protein misfolding and aggregation. After
QC functions of MGRN1, we provided additional information
on diverse cellular and physiological functions of MGRN1 in
the context of diseases and developmental abnormalities. In
last future prospective and key questions section of this review
elaborates hidden and versatile potential of MGRN1, which
may generate new interesting questions and also propose important implications of MGRN1 in the therapeutic intervention of neurodegeneration and aging.
Box 1
MGRN1: one protein, multiple functions; implications in diseases
▪ MGRN1, an E3 ubiquitin ligase, found to be involved in protein quality
control mechanism, providing cytoprotection against proteotoxic
insults
▪ Overview of MGRN1 gene, protein, its isoforms, and evolutionarily
conserved domains
▪ Interactions of MGRN1 with numerous proteins and its aberrant
functions/mutations linked with various diseases
▪ MGRN1 alleviates proteotoxicity generated by different cellular stress
conditions
▪ E3 ubiquitin ligase MGRN1 facilitates the elimination of misfolded/
non-native proteins from cells
▪ Cellular and physiological functions of MGRN1: pigment synthesis,
endosomal lysosomal trafficking, mitochondrial functioning, and
embryonic development
▪ Exploring future perspectives and therapeutic interventions of MGRN1
in cytoprotection, neurodegeneration and aging
Molecular Nature and Journey of MGRN1: a Link
to the Ubiquitin System
Mouse mahoganoid mutation related to darkening of coat color is associated with mahogunin gene lying on chromosome
16; mutations in this gene change the phenotypic effects of
agouti protein [12, 13]. Human MGRN1 full-length homologue identified is KIAA0544, and the precise cytogenetic
location is 16p13.3 [14]. Mahogunin encodes a C3HC4
Really Interesting New Gene (RING) domain protein and
supposed that it could retain E3 ubiquitin ligase activity on
the basis of sequence similarity [15]. In another study, it was
clearly shown that recombinant mahogunin exhibits E3 ubiquitin ligase activity with UBC5 (Ubiquitin-conjugating enzyme E2 5). This study also suggests that lack of function of
mahogunin can lead to substrate accumulation [16]. MGRN1
Cys residues deleted forms (Δ278–281 and Δ292–293) do
not retain auto-ubiquitination activity and UBC3 (ubiquitinconjugating enzyme E2 3), E2 protein also not demonstrates
auto-ubiquitination with MGRN1 E3 ubiquitin ligase [16, 17].
MGRN1 Gene Structure and Isoforms
In mice, MGRN1 is encoded by mahogunin gene lying on
chromosome 16. Alternative splicing of exons (12 and 17)
generates four MGRN1 isoforms. MGRN1 null mutant develops dark black color, but all four isoforms do not display
significant role in pigment-type switching. Isoforms I, II, and
III were well expressed in the brain, kidney, and heart, and
almost equal expression of all isoforms were observed in liver
tissue [18]. Expression profile of MGRN1 in brain tissue is
also high in both mouse and human and retains more than
90 % sequence similarity in its homologues, perhaps RING
domain region is also conserved in invertebrates and vertebrates genomes [16]. Human MGRN1 gene contains 17
exons, and alternative usage of exons (12, 16, and 17) produces different isoforms as shown in Fig. 2a, b. Melanoma
cells were shown to express four MGRN1 isoforms [19]. It
has also been shown in various cellular localization studies
that MGRN1 expresses in different cellular compartments
such as cytoplasm, plasma membrane, early endosome, and
nucleus [19, 20]. Recently, it has been shown that RNF157 is a
homologue of the mahogunin ring finger-1 E3 ligase involved
in the maintenance as well as regulation of dendritic growth in
cultured neurons and is also crucial for neuronal survival [21].
MGRN1 acts as an E3 ubiquitin ligase. Domain associated
with RING 2 (DAR2) is another evolutionary conserved domain, localized adjacent to RING finger domain. In
Arabidopsis, RING E3 ubiquitin ligase AtAIRP3/LOG2
(LOSS OF GDU 2) associates and ubiquitylates RD21
(Responsive to Dehydration 21) [22]. Arabidopsis thaliana
LOG2 and MGRN1 are functionally conserved, and mammalian MGRN1 interacts with plant membrane protein
GLUTAMINE DUMPER1 (GDU1) and further induces its
ubiquitylation [23]. As shown in Fig. 2c, d, various species
retain MGRN1 protein containing DAR2 and RING finger domain that exhibits a similar or conserved region. We know that
MGRN1 in various species do not represent an exact level of
similarity in RING finger and DAR2 domain region, still previous studies and current observation provides a clue that they
may have a potential to restore their cellular functions.
Recently, it has been shown that MGRN1 comprises a PSAP
motif, which is also conserved in different species. Interestingly,
PSAP motif of mouse MGRN1 binds with ubiquitin E2 variant
(UEV) domain of tumor susceptibility gene 101 (TSG101), a
component of the endosomal sorting complex required for transport I (ESCRT-I); site directed mutagenesis mutant of MGRN1,
i.e., MGRN1 (ASAA) did not bind with TSG101. PSAP motif
is absent in both the vertebrate family member MGRN2
(RNF157) and invertebrate MGRN homologues [24].
Earlier, it has been demonstrated that RING finger domain
is dedicated to numerous cellular functions, e.g., signal transduction, transcription, and protein ubiquitination [25–27].
Recently, it has also been observed that MGRN1 regulated
Mol Neurobiol
Fig. 2 Schematic diagram representing MGRN1: location, gene
structure, isoforms, organization, and sequence alignment. a, b
Location of MGRN1 gene on human chromosome 16 and genomic
structure of MGRN1 showing exons 1–17 (a); the linear structure of
different isoforms of MGRN1 generated by alternative splicing of 12
and 17 exons; details are explained in section (MGRN1 Gene Structure
and Isoforms) (b) [19, 24, 37]. c MGRN1 proteins from various species
showing the conservation of DAR2-RING region and PSAP motif [23,
107]. d Sequence alignment of MGRN1 proteins showing conservation
of DAR2 and Ring finger domain (Zebrafish (NP_956173.1), Pigeon
(XP_005508472.1), Xenopus (NP_001083558.1), Mouse (NP_
001239366.1), Human (NP_001135761.2), and Arabidopsis
(Q9S752.1)). Sequences were aligned using Clustal Omega and
visualized using Jalview [108, 109]. Default coloring scheme for
Clustal Omega in the Jalview program was used. Absolute conservation
of amino acids is depicted by asterisk (*). Score 0–9 followed by plus
sign represents amino acid conservation levels
Mc1r functional coupling to the cAMP cascade is independent
of ubiquitylation [19]. To gain insight into the RING finger
domain organization of MGRN1 and to better understand the
elementary steps for the regulation of MGRN1 ligase activity,
it is needful to obtain the crystal structure of MGRN1, which
is still not known. Since various sequence analysis reveal that
MGRN1 contains a RING finger domain [16, 17, 23], therefore, most likely in near future additional critical substrates
Mol Neurobiol
and hidden cellular functions of MGRN1 may be identified.
Compelling evidences indicate roles and functional implications of MGRN1 in neurodegenerative diseases. In the next
section, we elucidate and provide insight of MGRN1 into
disease-related proteins, which may also open new perspectives of critical substrates identification.
Molecular Functions of MGRN1
in Neurodegenerative Diseases
Recently published draft map of human proteome explores the
identification of proteins encoded by more than 17,000 genes
(near about 84 % of human protein coding genes) [28]. In
densely packed cellular environment, high protein concentration intensely fold up the fatal chances of their unwanted interactions with other native and non-native proteins which may
further lead to high probability of misfolding and aggregation
of existing and newly synthesized polypeptide chains [29, 30].
In previous few years, numerous studies have established a fact
that neuronal cells are more susceptible and vulnerable towards
misfolded proteins associated toxicity [31, 32]. Chaperones and
E3 ubiquitin ligases are the key players in cellular quality control system for the clearance of abnormal proteins while their
lack of function may cause various neurodegenerative diseases
[20, 33, 34]. MGRN1 is a putative RING finger domain containing E3 ubiquitin ligase and is widely expressed in different
tissues including brain [18].
Presence of vacuoles throughout the central nervous system
and further degenerative changes are the pivotal characteristics
of neurodegeneration [35, 36]. ESCRT-I component TSG 101
Ubiquitin E2 variant (UEV) domain binds with MGRN1
through its PSAP motif. Interaction of MGRN1 with TSG101
promotes its multimonoubiquitylation in a proteasome independent manner. MGRN1 null mouse suggests that neuronal
cells are specifically under higher risk as compared to other cell
types because of the disruptive endosomal–lysosomal system.
Table 1
diseases
Knockdown of MGRN1 deregulates endosome-to-lysosome
trafficking of epidermal growth factor receptor [37]. Most likely, under lack of MGRN1 functions, other E3 ubiquitin ligase
may take over the ubiquitination of TSG101 and inhibit the
formation of insoluble aggregates. TAL (also known as
LRSAM1) and MDM2 are two different E3 ubiquitin ligases,
which are involved in the ubiquitinylation of TSG101 protein
[38–40]. MGRN1 null mutants exhibit problems in pigmenttype switching, induce oxidative stress, and show mitochondrial dysfunction preceding neurodegeneration [41, 42].
Proteinaceous infectious particles prions (PrPSC) are generated from normal cellular isoform PrPC via post-translational
process and cause Creutzfeldt-Jakob and GerstmannStraussler-Scheinker diseases [43–45]. Previously, it has been
shown that MGRN1 interacts with both transmembrane isoform linked with prion disease (CtmPrP) and toxic cytosolic
form (cyPrP). Depletion of MGRN1 leads to altered lysosomal
morphology and contributes in neurodegeneration due to its
improper sequestration [46]. It is known that pathogenic forms
of prion protein originate from the conversion of its own normal form. But, it still remains central to research on prions to
know how these infective proteins lead to neuronal dysfunction
and death. An interesting observation detects that MGRN1 lack
of function or overexpression both do not induce prion proteins
like pathological symptoms on intracerebral inoculation of
Rocky Mountain Laboratory (RML) prion protein. Increase
or decrease in MGRN1 levels do not influence the progression
of transmissible spongiform encephalopathy in mice inoculated
with proteinaceous infectious prions particles (PrPSC) [47].
Nevertheless, mounting evidences suggest cellular quality
control components target prions for their clearance, and failure of such efforts generates severely toxic insults and mitochondrial dysfunction. Furthermore, this affects cellular processes such as post-Golgi vesicular trafficking of membrane
proteins [48–52]. One potential interpretation of these studies
is that loss of MGRN1 function plays a significant role in
neurodegenerative diseases, somewhere linked with
Enlisted representation of MGRN1 interacting proteins and molecular functions and aberrant function of MGRN1 linked with various
Interacting proteins of MGRN1
References Molecular functions of MGRN1
References MGRN1 mutations detrimental effects References
TSG101
[37]
Energy and insulin homeostasis
[15]
cyPrP/(Ctm)PrP
[46]
Embryonic patterning
[95]
MC1R/MC2R
Molecular chaperone
[19, 110]
[61]
Mitochondrial function
Endosomal trafficking
NEDD4
[111]
Melanocortin signaling
[113]
Cellular protein quality control
[61, 112]
Microtubule stability and mitotic [113]
spindle orientation
Spermatogenesis
[114]
α-tubulin
Expanded Polyglutamine Proteins [112]
Abnormal left-right axis patterning
[95]
[41]
[37]
Congenital heart defects
[95]
[19, 110]
Spongiform neurodegeneration
[16]
Male infertility
[114]
Mol Neurobiol
mitochondrial dysfunction, vacuoles formation and oxidative
stress via interaction with the components of cellular quality
control mechanism as summarized in Table 1. Perhaps these
speculations need further detailed study in near future.
MGRN1 Interaction with Cellular Protein Quality
Control Components Against Misfolded Aggregates:
Internal Competition or Defined Cooperation in QC
Pathway?
Each cell retains an ability to cope up against proteotoxic
insults and to sustain the proteostasis after broad cellular dysfunctions [53, 54]. However, much information is still unknown such as why various components of cellular quality
control pathways deposit [55, 56] or get sequestered [57, 58]
with abnormal protein aggregates? Whether such unwanted
interactions are healthier cooperative attempts to solve the
problem or these are misregulated detrimental competitive
trials to target misfolded proteins? Eukaryotic cells perform
cotranslational folding with the help of few molecular chaperones (Hsp40 and Hsp70). Cellular stress conditions induce a
major shift in intracellular distribution of chaperones such as
Hsp70; overexpression of Hsp70 provides cytoprotection
against various cellular insults and inhibits apoptosis [59,
60]. We observed in our previous study [61] that under distinct
cellular stress conditions, MGRN1 follows the similar profile
of Hsp70; both proteins colocalize and pivotally are recruited
with heat-denatured misfolded luciferase protein inclusions as
depicted in Fig. 3a, b.
Our earlier finding suggests the possible molecular
pathomechanism implication of MGRN1 in neurodegenerative
diseases; we extended our findings and observed that under
stress conditions, MGRN1 interacts with various cellular QC
components. Earlier, it has been observed that p62/SQSTM1
polyubiquitin-binding protein and light chain 3 (LC3) colocalizes with mutant huntingtin aggregates [62–64]. p62 generates
a stress response triggered by oxidative stress [65, 66]. Our
previous study also provides a clear insight that MGRN1 E3
ubiquitin ligase could also be recruited to p62 positive
polyubiquitinated perinuclear protein aggregates during the autophagy dysfunction as shown illustratively in Fig. 3c [20].
Proteasome inhibition leads to a strong colocalization of p62
with Hsp70 chaperone in perinuclear aggregates [67].
Altogether, these observations raise a convincing possibility
that MGRN1, p62, Hsp70, and probably a few components
of ubiquitin proteasome system (UPS) and autophagy somewhere crosstalk or interact to each other for the sorting and
effective clearance of misfolded proteins in dense cellular pool.
More recent work indicates that, probably, MGRN1 acts as
a crucial player in cellular QC pathway. The emerging functions of MGRN1 prompted us to further validate its QC capability against other misfolded proteins in a more defined
pattern. Expansions of polyglutamine proteins generates insoluble ubiquitin positive aggregates and serve as chief factor
in nine known expanded trinucleotide (CAG) repeat expansion disorders [68]. Ataxin-3 causes spinocerebellar ataxia
type-3, a neurodegenerative disease; it sequesters p62/
SQSTM1 in to expanded polyglutamine ataxin-3 aggregates
[69]. Similarly, expanded polyglutamine proteins sequester
various transcription factors including TATA box binding protein (TBP) and CREB binding protein (CBP) [70–72].
However, the precise molecular mechanism of neuronal loss
in Huntington disease (HD) is not known. Few studies elaborate that Htt aggregates repress p53-mediated transcription
and sequestration of NF-Y transcriptional factor and decrease
Hsp70 expression level [73–75].
To further explore the cellular QC function of MGRN1 in
cells, we performed colocalization studies with expanded
polyglutamine proteins. Surprisingly, we observed recruitment of MGRN1 with ubiquitin and p62 positive inclusions
of polyglutamine-expanded proteins both in in vitro and
in vivo models as represented diagrammatically in Fig. 3d.
Overexpression of MGRN1 provides cytoprotection against
toxicity linked with expanded polyglutamine proteins [34].
Previously, it has been studied that few E3 ubiquitin ligases
(E6-AP, CHIP, Gp78, and Hrd1) promote the degradation of
polyglutamine aggregation and suppress the toxicity mediated
by expanded polyglutamine proteins [76–79]. Above described studies support our recent finding that MGRN1 is a
putative E3 ubiquitin ligase that can target pathogenic expanded polyglutamine proteins for their elimination and able to
protect cells against poly (Q)-induced toxic events.
Distinct Molecular Functions of MGRN1: Multiple
Cellular Possibilities and Challenges
Previous detailed studies of MGRN1 gene and its encoded
product in E3 ubiquitin ligase have led to tremendous implications in neurodegenerative diseases and open new overlap
between the known interacting partners and genes. In the current review, we summarize and illustratively depict the major
cellular functions of MGRN1 as represented in Fig. 4: (a) role
in pigment switching, (b) MGRN1 involvement in endosomal
lysosomal trafficking, (c) MGRN1 depletion induced mitochondrial dysfunction, (d) irregular left-right axis patterning
in MGRN1 mutant mice. Substantial evidences from various
studies indicate that more imperative MGRN1 functions remain to be discovered.
MGRN1 mutant mice brains develop completely black
coat color linked with agouti signaling protein (ASIP); four
different MGRN1 isoforms usually do not represent significant functional difference in pigment-type switching [15, 16,
18]. Aberrant function of Mc1r and Agouti influence pigmentation in mice [18, 80]. Interaction of MGRN1 with Mc1r
Mol Neurobiol
Fig. 3 Recruitment of MGRN1 with misfolded protein aggregates and
molecular function in cellular quality control mechanism. a, b Numerous
diseases have been identified linked with abnormal aggregation of
misfolded proteins with chaperones and components of cellular QC
pathway. MGRN1 is recruited towards abnormal aggregates and
colocalizes with Hsp70 chaperone under unusual subsets of stress
inducing conditions (a); MGRN1 associates with heat stress conditions
induced luciferase protein inclusions in cells (b) [20]. c, d Accumulation
and aggregation of MGRN1 colocalizes with ubiquitin, p62, and Hsp70
inclusions in cells (c); furthermore, MGRN1 also recruits with ubiquitin
and p62 positive expanded polyglutamine proteins inclusions (Huntingtin
and Ataxin-3) in cells; similarly disruptive profile of MGRN1 was
observed in R6/2 transgenic mice model of Huntington disease (d) [34].
This unique feature of MGRN1 provides significant recognition of being
categorized as quality control E3 ubiquitin ligase most likely involved in
protein conformational disorders
generates pheomelanin via agouti signaling protein pathway.
But in the absence of MGRN1, Mc1r activation takes place
via alpha melanocyte stimulating hormone (α-MSH).
Exchange of GDP-GTP induces cAMP production that leads
to eumelanin (black/brown pigment) synthesis through
adenylyl cyclase [81–83].
Lysosomes are membrane bound acidic vacuoles, majorly
responsible for the recycling of damaged or poor organelles,
macromolecules, and proteins by endocytosis and autophagy.
Defects in lysosomal functions due to genetic mutations lead
to lysosomal storage disorders (LSDs) and also cause aging
and neurodegenerative diseases [84–86]. siRNA-mediated
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Fig. 4 A schematic diagram to represent MGRN1 loss of function
causing multifactorial disturbances or problems in various critical
cellular activities. a MGRN1 associates with Mc1r and produces
pheomelanin through agouti signaling pathway and lack of MGRN1
function or null mutants in mice generates dark coat color [15, 17, 18].
b MGRN1 null mutants demonstrate disturbed endolysosomal trafficking
and early enlarged endosomes. RING finger E3 ubiquitin ligase activity
of MGRN1 targets TSG101 for multiple mono-ubiquitination in
proteasomal independent manner [16, 24, 37]. c Depletion of MGRN1
induces mitochondrial dysfunction in cells and mice; this may act as a
causative factor in neurodegenerative diseases [41]. d Mutations in
MGRN1 produce complex congenital heart defects (CHD) and
abnormal LR patterning in mice embryos [95]. Overall, these studies
suggest that MGRN1 occupies a wide range of diverse cellular
functions and, therefore, needs an in-depth observation linked with
diseases
down regulation of endogenous MGRN1 modulates the
endolysosomal structures; cells appear with enlarged early
endosomes and disarrays endolysosomal trafficking of epidermal growth factor receptor (EGFR) [37]. MGRN1 null mutant
mice brains have altered profile of multimonoubiquitinated
TSG101 and may have insoluble TSG101 aggregates.
Probably, in MGRN1 null mice, aberrant function of normal
TSG101 contribute in the molecular pathomechanism of neurodegeneration associated with endolysosomal trafficking
[24]. In our previous study, we also observed that after autophagy inhibition, p62, ubiquitin, and Hsp70 chaperone colocalize with MGRN1 near to the nuclear periphery region.
Interestingly, it has earlier been shown that lysosomal Hsp70
stabilizes lysosomal membrane via binding with
endolysosomal anionic phospholipid bis (monoacylglycero)
phosphate (BMP) [87].
Ribosomes are also active in mitochondria and synthesize a
number of proteins. Oxidative stress results in the aggregation
of misfolded or damaged proteins in crowded cellular milieu
and overall potentially affects the numerous cellular functions
[88, 89]. Proteomic analysis of MGRN1 null mutant mice
brain reveal that mitochondrial proteins were significantly reduced with elevated oxidative stress. Complex IV (cytochrome c oxidase) level was dramatically reduced in
MGRN1 null mutant mice [41]. We also observed that
siRNA-mediated depletion of MGRN1 in cells make them
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more susceptible for mild oxidative stress and overexpression
of MGRN1 provide cytoprotection against oxidative stress
induced cell death [20].
Our existing knowledge about the mechanism of left-right
(LR) body axis determination during development period is
still limited. The accumulated evidences established a strong
role of few genes such as Nodal, EGF–CFC family of extracellular factors, Lefty1, Lefty2, and transforming-β-related
signaling molecules in LR axis determination [90–94].
Recently, interesting finding has also come to insight
concerning the important role of MGRN1 in left-right (LR)
signaling cascade and embryonic patterning determination.
This study elaborates that MGRN1 mutant embryos exhibit
complex congenital heart defects (CHD) and abnormal LR
patterning [95]. However, more refined new crucial substrates
finding studies targeting the ubiquitin ligase activity of
MGRN1 implicated in normal left-right (LR) axis embryo
developments are imperatively needful. It is also important
to recognize the proteins that significantly crosstalk to
MGRN1 and also to know how their aberrant forms directly
or indirectly generate moderate risk of diseases by affecting
MGRN1 diverse cellular functions.
Future Prospective and Key Questions
Different neurodegenerative diseases share common cellular and molecular problem of misfolded proteins aggregation and inclusion bodies formation. In previous studies, it
has been shown that ubiquitin, proteasome, autophagy
pathway components, molecular chaperones, nascent polypeptide chains, and transcription factors are chiefly present
with aggregates or inclusion bodies [29]. Few interesting
reports indicate that overwhelmed aggregation of abnormal
proteins compromises the proteolytic functions of both
ubiquitin proteasome system and autophagy pathway [96,
97]. Perturbations in the function of proteolytic machinery
generate a major challenge to resolve or find a possible
cure against the problem of protein aggregation in neurodegenerative diseases. The blood–brain barrier (BBB) is a
highly selective permeability barrier, which restricts the
passage of numerous drugs and major molecules and essentially, this is another fundamental challenge to deliver
drugs across the blood–brain barrier [98, 99]. Still, the
pivotal reason why neuronal cells are not capable to eliminate visible abnormal protein aggregates and how their
formation contributes in proteotoxicity generation and
neuropathogenesis is not well known.
Now, another important aspect is needed to be addressed to the neuroprotective agents or molecular tactics
that could be used for the suppression of neurotoxic load
caused by protein misfolding aggregation? Normally, proteins are routinely cleared by ubiquitin proteasome system
and autophagy pathway. Chaperones promote the folding
of non-native proteins and increase their further chances
of survival in dense crowded milieu. It is very important
to search inducers of molecular chaperones, which can
prevent or suppress misfolding of proteins and this strategy may be useful as therapeutic intervention in neurodegeneration and aging [100–102]. Cooperative functions of
autophagy and ubiquitin proteasome system can serve as
an integral part of clearance mechanism and may heal the
detrimental cellular loss induced by proteotoxic insults
[103–105]. One of the key tactics is to find out novel
chemical inducers which can specifically promote protein
degradation, and this strategy can be also useful to keep
low basal levels of over accumulated abnormal proteins
[106]. Understanding the detailed physiological functions
of protein quality control mechanism and its hidden possible mechanisms in the causation can help in the prevention of neurotoxic load caused by protein misfolding
aggregation.
An increasing body of evidence opens few first order
questions about the cellular and molecular nature of
MGRN1 and about its function as an E3 ubiquitin ligase.
But how does the aberrant function of MGRN1 interplay
significant role in neurodegeneration still remain obscures? How does the E3 ubiquitin ligase activity of
MGRN1 influence the endogenous levels of crucial substrates, mitochondrial dysfunction, and misfolded protein
aggregate formation needs further detailed analyses and
careful interpretation? In principle, detailed molecular
characterization of MGRN1 can exert new significant
findings to influence the cellular PQC pathway and most
likely opens new hidden potential of this novel gene in
aging and neurodegeneration. However, it remains less
clear how the MGRN1 is activated for the misfolded
protein recruitment cascade along with other components
of UPS and autophagy pathway? The lessons learned
from previous findings already reveal that MGRN1 could
serve as a wide range of essential cellular functions. But
what are the key coplayers of MGRN1; which other E3
ubiquitin ligases can execute similar functions in the
macromolecular crowding need detailed study and
implementation.
Over the past few years, incredible progress has been made
in interpreting the role of E3 ubiquitin ligases in neurodegenerative diseases. Now, it is important to design new drugs,
based on the defective processing caused by the aberrant functions of these E3 ubiquitin ligases. MGRN1 loss of function
could disturb the endolysosomal trafficking; however, the detailed molecular pathomechanism is unknown. In near future,
identification of MGRN1 crystal structure may reveal more
about the role of its E3 ubiquitin ligase activity, substrate
binding capacity, and improve our understanding about how
MGRN1 mutations generate a wide variety of functional
Mol Neurobiol
tribulations in cells. The mechanistic basis of these analyses of
MGRN1 most likely opens the hidden high versatile potential
of this novel protein to further improve our understanding to
protect cells from proteotoxic old or damaged proteins.
11.
12.
13.
Acknowledgments This work was supported by the Department of
Biotechnology, Government of India. AM was supported by
Ramalinganswami Fellowship (BT/RLF/Reentry/11/2010) and Innovative Young Biotechnologist Award (IYBA) scheme (BT/06/IYBA/
2012) from the Department of Biotechnology, Government of India.
AU was supported by a research fellowship from the Council of Scientific
and Industrial Research-University Grants Commission (CSIR-UGC),
Government of India. The authors would like to thank Mr. Bharat Pareek
for his technical assistance and the entire lab management during the
manuscript preparation. We apologize to various authors whose work
could not be included due to space limitations.
14.
15.
16.
Compliance with Ethical Requirements
Conflict of Interest The authors declare that they have no competing
interests.
17.
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