RNF156, MGRN1 E3 ubikitiiniligaasi (Mahoquin Ring Finger 1)

Neuroprotektiivinen E3-ubikitiiniligaasi, alfa-tubuliinin stabilaattori,  mitoottisen sukkulan orientoija .  Kompromittoitunut prionitaudeissa ja aivoon iskevissä viruksissa (HIV-1) .

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

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 28475871
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. With aging, the neuroprotective e3 ligase MGRN1 relocates from the cytosol to the nucleus of neurons, where it associates with chromatin and potentiates the cellular response to proteotoxic stress. This nuclear shift is due to a proteasome impairment dependent increase of a monoubiquitinated form of MGRN1.
6. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy.
7. Mahogunin-mediated alpha-tubulin ubiquitination via noncanonical K6 linkage regulates microtubule stability and mitotic spindle orientation.
8. data suggest that MGRN1 selectively targets misfolded proteins for degradation and may exhibit viable therapeutic potential for the treatment of spongiform neurodegeneration
9. It therefore seems probable that the role of MGRN1 in the adrenal relates to the trafficking and/or degradation of the melanocortin 2 receptor.
10. 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