A Legionella pneumophila Kinase Phosphorylates the Hsp70 Chaperone Family to Inhibit Eukaryotic Protein Synthesis

Steven M Moss; Isabelle R Taylor; Davide Ruggero; Jason E Gestwicki; Kevan M Shokat; Shaeri Mukherjee

doi:10.1016/j.chom.2019.01.006

A Legionella pneumophila Kinase Phosphorylates the Hsp70 Chaperone Family to Inhibit Eukaryotic Protein Synthesis

Cell Host Microbe. 2019 Mar 13;25(3):454-462.e6. doi: 10.1016/j.chom.2019.01.006. Epub 2019 Feb 28.

Authors

Steven M Moss¹, Isabelle R Taylor², Davide Ruggero³, Jason E Gestwicki², Kevan M Shokat⁴, Shaeri Mukherjee⁵

Affiliations

¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: kevan.shokat@ucsf.edu.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; George Williams Hooper Foundation, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: shaeri.mukherjee@ucsf.edu.

Abstract

Legionella pneumophila (L.p.), the microbe responsible for Legionnaires' disease, secretes ∼300 bacterial proteins into the host cell cytosol. A subset of these proteins affects a wide range of post-translational modifications (PTMs) to disrupt host cellular pathways. L.p. has 5 conserved eukaryotic-like Ser/Thr effector kinases, LegK1-4 and LegK7, which are translocated during infection. Using a chemical genetic screen, we identified the Hsp70 chaperone family as a direct host target of LegK4. Phosphorylation of Hsp70s at T495 in the substrate-binding domain disrupted Hsp70's ATPase activity and greatly inhibited its protein folding capacity. Phosphorylation of cytosolic Hsp70 by LegK4 resulted in global translation inhibition and an increase in the amount of Hsp70 on highly translating polysomes. LegK4's ability to inhibit host translation via a single PTM uncovers a role for Hsp70 in protein synthesis and directly links it to the cellular translational machinery.

Keywords: Hsp70; Legionella pneumophila; kinase; phosphorylation; translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Eukaryotic Cells / metabolism*
Eukaryotic Cells / microbiology
HSP70 Heat-Shock Proteins / metabolism*
Host-Pathogen Interactions*
Legionella pneumophila / enzymology*
Legionnaires' Disease / microbiology
Phosphorylation
Phosphotransferases / metabolism*
Protein Biosynthesis*
Protein Processing, Post-Translational*
Virulence Factors / metabolism

Substances

HSP70 Heat-Shock Proteins
Virulence Factors
Phosphotransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding