ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Clearance of Arsenite-Induced Stress Granules.

Ankit Turakhiya, Susanne R Meyer, Gabriella Marincola, Stefanie Böhm, Jens T Vanselow, Andreas Schlosser, Kay Hofmann, Alexander Buchberger

Journal: Molecular cell 2019;70(5):906-919.e7

PMID: 29804830

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Abstract

Stress granules (SGs) are cytoplasmic assemblies of mRNPs stalled in translation initiation. They are induced by various stress conditions, including exposure to the environmental toxin and carcinogen arsenic. While perturbed SG turnover is linked to the pathogenesis of neurodegenerative diseases, the molecular mechanisms underlying SG formation and turnover are still poorly understood. Here, we show that ZFAND1 is an evolutionarily conserved regulator of SG clearance. ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. In the absence of ZFAND1, SGs lack the 26S proteasome and p97, accumulate defective ribosomal products, and persist after arsenite removal, indicating their transformation into aberrant, disease-linked SGs. Accordingly, ZFAND1 depletion is epistatic to the expression of pathogenic mutant p97 with respect to SG clearance, suggesting that ZFAND1 function is relevant to the multisystem degenerative disorder IBMPFD/ALS.

Address: Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.; Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.; Institute for Genetics, University of Cologne, 50674 Cologne, Germany.; Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany. Electronic address: [email protected].

DOI: 10.1016/j.molcel.2018.04.021