ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

Abstract

Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

Chromosome territories and the global regulation of the genome

“…136 It has both DNA and RNA binding properties and is involved in a wide range of processes ranging from cell survival to association at S/MAR chromatin loop anchor sites to a variety of functions involved in RNA metabolism including RNA splicing, mRNA assembly/stabilization, RNA export/retention, and viral RNA regulation. 107,108,123,[137][138][139][140][141][142][143][144][145] Consistent with these findings, yeast two hybrid screening identified interactions with a constellation of proteins involved in DNA replication/repair, transcription, and RNA splicing. 66 A recent transcriptome and interactome analysis revealed over 100 proteins that bind matrin 3 (prominently including proteins associated with RNA processing/splicing 146 ).…”

“…Matrin 3 is an acidic ~120 kDa nuclear matrix protein that is among the major proteins of isolated nuclear matrix based on two‐dimensional (2‐D) gel separations . It has both DNA and RNA binding properties and is involved in a wide range of processes ranging from cell survival to association at S/MAR chromatin loop anchor sites to a variety of functions involved in RNA metabolism including RNA splicing, mRNA assembly/stabilization, RNA export/retention, and viral RNA regulation . Consistent with these findings, yeast two hybrid screening identified interactions with a constellation of proteins involved in DNA replication/repair, transcription, and RNA splicing .…”

“…4,12 The potential physiological roles that matrin 3 plays in nuclear organization and function are further emphasized by the recent findings connecting mutations in the matrin 3 gene (MATR3) to the diseases ALS, distal myopathy, and left ventricular outflow tract obstruction (LVOTO), a common congenital heart defect. 124,141,[146][147][148][149] Within the nuclear matrix, the nuclear lamina-the network of peripheral proteins surrounding the inner nuclear membrane-has also been posited as a major factor in the organization of the genome. 61,[150][151][152][153][154][155][156] The major proteins of the nuclear lamina are lamins A, B, and C. These bind to a myriad of other proteins involved in many nuclear functions.…”

“…Based on these findings and similar properties of these two proteins, it was proposed that SAF‐A and matrin 3 are major components of a nuclear scaffolding structure that serve as dynamic assembly centers for the organization of functional neighborhoods of genomic function in the cell nucleus . The potential physiological roles that matrin 3 plays in nuclear organization and function are further emphasized by the recent findings connecting mutations in the matrin 3 gene (MATR3) to the diseases ALS, distal myopathy, and left ventricular outflow tract obstruction (LVOTO), a common congenital heart defect …”

ALS Genes in the Genomic Era and their Implications for FTD

“…It was found that MATR3 can be sequestered to cytoplasmic aggregates by mutant FUS (Figure 1 and Box 2) [10,57]. Another study demonstrated that MATR3 mutations lead to nuclear export defects of TDP-43 and FUS mRNA [58]. Rare MATR3-positive cytoplasmic inclusions were observed in an ALS patient carrying a C9orf72 repeat expansion, potentially unravelling a common cellular pathway for both genes, although these observations need confirmation and further functional studies [10].…”