2. Academic Validation
  3. PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction

PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction

  • Autophagy. 2024 Oct;20(10):2221-2237. doi: 10.1080/15548627.2024.2361574.
Yun-Da Chen 1 2 3,  Xiu-Ping Lin 1 2 3,  Zi-Lun Ruan 1 2 3,  Mi Li 1 2 3,  Xue-Mei Yi 1 2 3,  Xu Zhang 1 2 3,  Shu Li 1 2 3,  Hong-Bing Shu 1 2 3
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, College of Life Sciences, Wuhan, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 3 Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences, Wuhan, China.
PMID: 39316746 DOI: 10.1080/15548627.2024.2361574
Abstract

Dysregulation in protein homeostasis results in accumulation of protein aggregates, which are sequestered into dedicated insoluble compartments so-called inclusion bodies or aggresomes, where they are scavenged through different mechanisms to reduce proteotoxicity. The protein aggregates can be selectively scavenged by macroautophagy/Autophagy called aggrephagy, which is mediated by the autophagic receptor SQSTM1. In this study, we have identified PLK2 as an important regulator of SQSTM1-mediated aggregation of polyubiquitinated proteins. PLK2 is upregulated following Proteasome inhibition, and then associates with and phosphorylates SQSTM1 at S349. The phosphorylation of SQSTM1 S349 strengthens its binding to KEAP1, which is required for formation of large SQSTM1 aggregates/bodies upon Proteasome inhibition. Our findings suggest that PLK2-mediated phosphorylation of SQSTM1 S349 represents a critical regulatory mechanism in SQSTM1-mediated aggregation of polyubiquitinated proteins.

Keywords

PLK2; Phosphorylation; SQSTM1/p62; polyubiquitination; proteasome; protein aggregation.

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