Neuroprotektiivinen E3 ubikitiiniligaasi MGRN1(RNF156) (16p13.3)

 RNF156, MGRN1 (16p13.3), Mahogunin Ring Finger-1
Expr. Spleen, brain.
https://www.ncbi.nlm.nih.gov/gene/?term=RNF156

Preferred Names

E3 ubiquitin-protein ligase MGRN1

Names

RING finger protein 156

RING-type E3 ubiquitin transferase MGRN1

mahogunin RING finger protein 1

mahogunin ring finger 1, E3 ubiquitin protein ligase

probable E3 ubiquitin-protein ligase MGRN1

Conserved Domains (3) summary

PHA02929
Location:232 → 331

PHA02929; N1R/p28-like protein; Provisional

• The poxviral RING protein p28 is a ubiquitin ligase that targets ubiquitin to viral replication factories.J. Virol. 2005 Jan ; 79(1):597-601
• Genome of deerpox virus.J. Virol. 2005 Jan ; 79(2):966-77
• Genome comparison of a nonpathogenic myxoma virus field strain with its ancestor, the virulent Lausanne strain.J. Virol. 2009 Mar ; 83(5):2397-403

TIGR00599
Location:273 → 449

rad18; DNA repair protein rad18.All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

pfam13920
Location:274 → 319

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)

 

Related articles in PubMed

1. MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport. Mukherjee R, et al. Traffic, 2017 Dec. PMID 28902452
2. Mahogunin ring finger-1 (MGRN1) suppresses chaperone-associated misfolded protein aggregation and toxicity. Chhangani D, et al. Sci Rep, 2013. PMID 23756845, Free PMC Article
3. Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system. Mukherjee R, et al. FASEB J, 2019 Feb. PMID 30230921
4. Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival. Benvegnù S, et al. Mol Cell, 2017 May 4. PMID 28475871A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.
5. DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA. Tang Q, et al. Oncotarget, 2016 Sep 27. PMID 27577081, Free PMC Article

1. depletion of MGRN1 activity may hamper physiologically important processes like mitochondrial movement in neuronal processes and intracellular transport of ligands through the endosomal pathway thereby contributing to the pathogenesis of neurodegeneration in certain types of prion diseases
2. In a heterologous expression system, MC1R-dependent Arrestins B ubiquitination was enhanced by overexpression of MGRN1 and was impaired by siRNA-mediated MGRN1 knockdown thus pointing to MGRN1 as the responsible E3-ligase.
3. Hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with breast cancer.
4. Regulation of Mfn1 by MGRN1 and the proteasome modulates mitochondrial fusion.
5. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy.
6. Mahogunin-mediated alpha-tubulin ubiquitination via noncanonical K6 linkage regulates microtubule stability and mitotic spindle orientation.
7. data suggest that MGRN1 selectively targets misfolded proteins for degradation and may exhibit viable therapeutic potential for the treatment of spongiform neurodegeneration
8. It therefore seems probable that the role of MGRN1 in the adrenal relates to the trafficking and/or degradation of the melanocortin 2 receptor.
9. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)D

Select item 310898071.

Chronic and age-dependent effects of the spongiform neurodegeneration-associated MGRN1 E3 ubiquitin ligase (RFN156), Mahoquin Ring finger, Chr.11)    on mitochondrial homeostasis.

Gunn TM, Silvius D, Lester A, Gibbs B.

Mamm Genome. 2019 May 14. doi: 10.1007/s00335-019-09802-7. [Epub ahead of print]

Spongiform encephalopathy is an intriguing yet poorly understood neuropathology characterized by vacuoles, demyelination, and gliosis.
 It is observed

• in patients with prion disease, 
• primary mitochondrial disease,
•  HIV-1 infection of the brain, and 
• some inherited disorders,

 but the underlying mechanism of disease remains unclear. The brains of mice lacking the MGRN1 E3 ubiquitin ligase develop vacuoles by 9 months of age. MGRN1-dependent ubiquitination has been reported to regulate mitofusin 1 and GP78, suggesting MGRN1 may have a direct effect on mitochondrial homeostasis. Here, we demonstrate that some MGRN1 localizes to mitochondria, most likely due to N-myristoylation, and mitochondria in cells from Mgrn1 null mutant mice display fragmentation and depolarization without recruitment of the parkin E3 ubiquitin ligase. The late onset of pathology in the brains of Mgrn1 null mutant mice suggests that a further, age-dependent effect on mitochondrial homeostasis may be required to trigger vacuolation. Parkin protein and mRNA levels showed a significant decline in the brains of Mgrn1 null mutant mice by 12 months of age. To test whether loss of parkin triggers vacuolation through a synergistic effect, we generated Mgrn1; parkin double mutant mice. By 1 month of age, their brains demonstrated more severe mitochondrial dysfunction than Mgrn1 null mutants, but there was no effect on the age-of-onset of spongiform neurodegeneration. Expression of the ATF4 transcription factor, a key regulator of the mitochondrial stress response, also declined in the brains of aged Mgrn1 null mutant mice. Together, the data presented here indicate that loss of MGRN1 has early, direct effects on mitochondrial homeostasis and late, indirect effects on the ability of cells to respond to mitochondrial stress.DOI:10.1007/s00335-019-09802-7