Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB

Abstract

Matrin3 is an RNA- and DNA-binding nuclear matrix protein found to be associated with neural and muscular degenerative diseases. A number of possible functions of Matrin3 have been suggested, but no widespread role in RNA metabolism has yet been clearly demonstrated. We identified Matrin3 by its interaction with the second RRM domain of the splicing regulator PTB. Using a combination of RNAi knockdown, transcriptome profiling and iCLIP, we find that Matrin3 is a regulator of hundreds of alternative splicing events, principally acting as a splicing repressor with only a small proportion of targeted events being co-regulated by PTB. In contrast to other splicing regulators, Matrin3 binds to an extended region within repressed exons and flanking introns with no sharply defined peaks. The identification of this clear molecular function of Matrin3 should help to clarify the molecular pathology of ALS and other diseases caused by mutations of Matrin3.

RETRACTED ARTICLE: Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype

“…It has two RNA recognition motifs in tandem, two zinc finger domains, a nuclear localization signal, a nuclear export signal, and a membrane retention signal [10]. Matrin 3 has roles in retention of hyper-edited RNA to the nucleus [35], DNA repair due to double strand breaks [26], alternative splicing [4], and even neuronal death due to NMDA-receptor activation [8]. We have previously shown that disease-causing mutations in Matrin 3 do not strikingly alter normal nuclear localization of the protein, nor does the protein form inclusions in H4 neuroglioma and Chinese Hamster Ovary cells [7].…”

Large-scale remodeling of a repressed exon ribonucleoprotein to an exon definition complex active for splicing

“…These were the expected PTBP1 and two proteins known to be PTBP1 corepressors in the repression of other exons, RAVER1 and MBNL1 (Figure 4B right panel; Supplementary file 1) (Joshi et al, 2011; Gromak et al, 2003; Gooding et al, 2013). Another known PTBP1 interacting protein, MATRIN3, was inconsistently found in the exon complexes (Coelho et al, 2015). …”

“…Work from the Smith and Curry labs has defined a precise interaction of a peptide in RAVER1 with RRM2 of PTBP1 (Joshi et al, 2011). The protein MATRIN3 has the same peptide and appears to make a PTBP1 interaction similar to RAVER1 (Joshi et al, 2011; Coelho et al, 2015). Although MATRIN3 is present in some of our complexes, its co-binding with PTBP1 was less clear than RAVER1 and MBNL1.…”

Vulnerability of newly synthesized proteins to proteostasis stress

“…For example, CDK1 is a master regulator of mitosis and is responsible for the phosphorylation of a large number of substrates (for a review, see Domingo-Sananes et al, 2011), FEN1 is essential for excision DNA repair (for a review, see Tsutakawa et al, 2011), and MATR3 and TDP-43 are RNA-binding proteins that regulate mRNA splicing and possibly other RNA metabolic processes (Coelho et al, 2015;Polymenidou et al, 2011). Partial loss of function of these activities and potentially many others could compromise cellular function or viability.…”