MARK4 enhances stress granule formation and increases tau accumulation

Abstract

Stress granules (SGs) are membrane-less organelles that are formed in response to cellular stress. SG formation protects cells against stress; however, their dysregulation and longer persistence may disrupt proteostasis. Abnormal activity of Microtubule-affinity regulating kinase 4 (MARK4) has been linked to cancer and Alzheimers disease. Here, we report that MARK4 is a component of SGs and enhances SG formation. MARK4 is found in SGs in mammalian cultured cells and primary neurons with T-cell intracellular antigen 1 (TIA1). MARK4 expression enhances SG formation induced by hydrogen peroxide. The spacer domain of MARK4 mediates its localization to SGs, and its kinase activity is required for the enhancement of SG formation. MARK4 suppresses TIA1 dimerization induced by hydrogen peroxide. Furthermore, we found that MARK4 and TIA1 synergistically promoted tau accumulation in cultured cells, and knockdown of a fly TIA1 homolog suppressed tau toxicity in a Drosophila model. These results indicate that MARK4 regulates TIA1 and SG formation and suggest that MARK4 and TIA1 synergistically contribute to tau toxicity.