C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease.

Acta Neuropathologica Communications
John L GoodierJose Luis García-Pérez

Abstract

A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing ...Continue Reading

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Citations

Sep 10, 2020·International Journal of Molecular Sciences·Sara BachillerRocío Ruiz
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Litian ZhangLiang Chen
Apr 17, 2021·Journal of Neuropathology and Experimental Neurology·Benjamin C CreekmoreEdward B Lee

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Datasets Mentioned

BETA
GSE67196
SRP098831
BC005067
BC101117

Methods Mentioned

BETA
nucleotide
GTPases
GTPase
co-IP
transfections
PCR
co-immunoprecipitation
co-IPs
immunoprecipitation
ubiquitination

Software Mentioned

Scaffold
Mascot
DAVID
Clustal Omega
NIS
TETranscripts
Elements AR
Illumina Expansion Hunter
Proteome Discoverer
DAVID Functional Annotation Tool (

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