Universität zu Köln

Ganesan, Raja, Hos, Nina Judith, Gutierrez, Saray, Fischer, Julia, Stepek, Joanna Magdalena, Daglidu, Evmorphia, Kroenke, Martin and Robinson, Nirmal ORCID: 0000-0002-7361-9491 (2017). Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy. PLoS Pathog., 13 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S. Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S. Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S. Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy. The activation of AMPK is regulated by LKB1 in a cytosolic complex containing Sirt1 and LKB1, where Sirt1 is required for deacetylation and subsequent activation of LKB1. S. Typhimurium infection targets Sirt1, LKB1 and AMPK to lysosomes for rapid degradation resulting in the disruption of the AMPK-mediated regulation of mTOR and autophagy. The degradation of cytosolic Sirt1/LKB1/AMPK complex was not observed with two mutant strains of S. Typhimurium, Delta ssrB and.ssaV, both compromising the pathogenicity island 2 (SPI2). The results highlight virulence factor-dependent degradation of host cell proteins as a previously unrecognized strategy of S. Typhimurium to evade autophagy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ganesan, Raja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hos, Nina Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutierrez, Saray UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Stepek, Joanna Magdalena UNSPECIFIED UNSPECIFIED UNSPECIFIED Daglidu, Evmorphia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroenke, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Robinson, Nirmal UNSPECIFIED orcid.org/0000-0002-7361-9491 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-241024
DOI:	10.1371/journal.ppat.1006227
Journal or Publication Title:	PLoS Pathog.
Volume:	13
Number:	2
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACTIVATED PROTEIN-KINASE; PATHOGENICITY ISLAND 2; III SECRETION SYSTEM; ENERGY HOMEOSTASIS; HOST-DEFENSE; SIRTUIN 1; AMPK; CELL; MACROPHAGES; SURVIVAL Multiple languages Microbiology; Parasitology; Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24102