The role of MATRIN3 (MATR3) in innate immune response

Abstract MATR3, one of the most abundant inner nuclear matrix proteins, is implicated in amyotrophic lateral sclerosis (ALS) and distal myopathy. MATR3 has been reported to have both DNA- and RNA-binding abilities. However, it is not understood mechanistically how mutation of MATR3 leads to ALS pathogenesis. To understand its loss of function effects, we mutated MATR3 in the human HAP1 cell line using CRISPR/Cas9 technology. Using two different RNA sequencing methods, Oxford Nanopore Technologies and Illumina, we discovered the upregulation of many interferon-stimulated genes (ISGs) in MATR3-deficient HAP1 cells. Furthermore, we have validated these results by Nanostring technology. Next, we hypothesized that HAP1 cells may be responding to endogenous double-stranded RNAs. Interestingly, we observed similar amounts of dsRNA in both MATR3 knock-out (KO) and wildtype (WT) cells which suggests that indeed intracellular dsRNAs are present and could be stimulating HAP1 cells; however, it is not the case that MATR3 KO cells are stimulated because they are producing significantly more dsRNAs. Currently, we are investigating whether and which RNA sensors are activated in MATR3 KO cells. Also, we are investigating whether MATR3’s DNA- and/or RNA-binding abilities are responsible for the innate immune response. Accordingly, we plan to perform CUT & RUN and photoactivatable ribonucleoside enhanced crosslinking and immunoprecipitation (PAR-CLIP) respectively, in HAP1 cells. Altogether, our results illustrate that MATR3 is a novel negative regulator of the innate immune response. This work was supported by the Intramural Research Program of NIAID, NIH. This work was supported by the Intramural Research Program of NIAID, NIH.