Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy

Ryosuke Ishimura; Keiji Tanaka; Masaaki Komatsu

doi:10.1016/j.febslet.2014.01.045

Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy

FEBS Lett. 2014 Mar 3;588(5):822-8. doi: 10.1016/j.febslet.2014.01.045. Epub 2014 Feb 1.

Authors

Ryosuke Ishimura¹, Keiji Tanaka², Masaaki Komatsu³

Affiliations

¹ Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
² Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
³ Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Department of Biochemistry, School of Medicine, Niigata University, Niigata 951-8510, Japan. Electronic address: [email protected].

PMID: 24492006
DOI: 10.1016/j.febslet.2014.01.045

Abstract

Upon infection of a cell by Salmonella, p62/Sqstm1 assembles on the microbes; simultaneously, p62/Sqstm1 is phosphorylated at Ser351, leading to inactivation of Keap1, which is responsible for degrading Nrf2. Thus, cytoprotective Nrf2 targets are induced at the same time that autophagosomes entrap the microbes (xenophagy). However, the detailed role of p62/Sqstm1 during xenophagy has remained unclear. Here we show that translocation of p62/Sqstm1 to invasive Salmonella precedes Ser351 phosphorylation. Furthermore, in addition to Ser351 phosphorylation, oligomerization of p62/Sqstm1 is also required for localization of Keap1 onto microbes, which is followed by Nrf2 activation. Our data reveal the sequential dynamics of p62/Sqstm1 in response to bacterial infection.

Keywords: Autophagy; Keap1; Nrf2; Xenophagy; p62.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Adaptor Proteins, Signal Transducing / physiology*
Animals
Autophagy*
Cells, Cultured
Cytoskeletal Proteins / metabolism
Heat-Shock Proteins / physiology*
Host-Pathogen Interactions
Kelch-Like ECH-Associated Protein 1
Mice
NF-E2-Related Factor 2 / metabolism*
Phosphorylation
Protein Binding
Protein Multimerization
Protein Processing, Post-Translational
Protein Structure, Tertiary
Protein Transport
Salmonella Infections / metabolism*
Salmonella Infections / pathology
Salmonella typhimurium / physiology*
Sequestosome-1 Protein
Ubiquitin / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cytoskeletal Proteins
Heat-Shock Proteins
Keap1 protein, mouse
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Sequestosome-1 Protein
Sqstm1 protein, mouse
Ubiquitin