Proteomics elucidating physiological and pathological functions of TDP‐43

Abstract Trans‐activation response DNA binding protein of 43 kDa (TDP‐43) regulates a great variety of cellular processes in the nucleus and cytosol. In addition, a defined subset of neurodegenerative diseases is characterized by nuclear depletion of TDP‐43 as well as cytosolic mislocalization and aggregation. To perform its diverse functions TDP‐43 can associate with different ribonucleoprotein complexes. Combined with transcriptomics, MS interactome studies have unveiled associations between TDP‐43 and the spliceosome machinery, polysomes and RNA granules. Moreover, the highly dynamic, low‐valency interactions regulated by its low‐complexity domain calls for innovative proximity labeling methodologies. In addition to protein partners, the analysis of post‐translational modifications showed that they may play a role in the nucleocytoplasmic shuttling, RNA binding, liquid‐liquid phase separation and protein aggregation of TDP‐43. Here we review the various TDP‐43 ribonucleoprotein complexes characterized so far, how they contribute to the diverse functions of TDP‐43, and roles of post‐translational modifications. Further understanding of the fluid dynamic properties of TDP‐43 in ribonucleoprotein complexes, RNA granules, and self‐assemblies will advance the understanding of RNA processing in cells and perhaps help to develop novel therapeutic approaches for TDPopathies.