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Review
. 2024 Jun 26;52(3):961-972.
doi: 10.1042/BST20220585.

The role of Matrin-3 in physiology and its dysregulation in disease

Macy L Sprunger  1 , Meredith E Jackrel  1
Affiliations
Review

The role of Matrin-3 in physiology and its dysregulation in disease

Macy L Sprunger et al. Biochem Soc Trans. .

Abstract

The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.

Keywords: Matrin-3; RNA-binding proteins; amyotrophic lateral sclerosis; biomolecular condensates; intrinsically disordered proteins; neurodegeneration.

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Figures

Figure 1:
Figure 1:
MATR3 is a disordered DNA- and RNA-binding protein. (Top) Domain map of MATR3. The zinc finger motifs (Z1–2), RNA recognition motifs (RRM1–2), and nuclear localization sequence (NLS) are highlighted. Adult-onset neurological disorder associated mutations are shown in black, childhood-onset neurological disorder associated mutations are shown in red, and * indicates a patient-associated mutation which may not be causative of disease. (Bottom) Cartoon structure of human MATR3 predicted by Alpha Fold with RRMs shown in blue, zinc fingers shown in teal, and NLS shown in navy.
Figure 2:
Figure 2:
Involvement of MATR3 in physiological processes. Cellular view of MATR3-linked processes. In the nucleus, MATR3 is implicated in transcription, DNA damage response, splicing, mRNA export, nuclear retention of hyper-edited RNA, and regulation of paraspeckle formation. In the cytoplasm, MATR3 is implicated in RNA silencing, RNA degradation at P bodies, mRNA stabilization, and may localize to stress granules.
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