Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival

Yinjuan Song; Xin Ge; Yulan Chen; Tariq Hussain; Zhengmin Liang; Yuhui Dong; Yuanzhi Wang; Chengyuan Tang; Xiangmei Zhou

doi:10.1080/15548627.2021.1987671

Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival

Autophagy. 2022 Jun;18(6):1401-1415. doi: 10.1080/15548627.2021.1987671. Epub 2021 Oct 31.

Authors

Yinjuan Song¹, Xin Ge¹, Yulan Chen¹, Tariq Hussain^{1

2}, Zhengmin Liang¹, Yuhui Dong¹, Yuanzhi Wang¹, Chengyuan Tang³, Xiangmei Zhou¹

Affiliations

¹ Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
² College of Veterinary Sciences, The University of Agriculture Peshawar, Peshawar, Pakistan.
³ Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that Mycobacterium bovis (M. bovis) utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. M. bovis is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that M. bovis induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis. Moreover, the survival of M. bovis in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances M. bovis growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of M. bovis in the host.Abbreviations: BMDM: mouse bone marrow-derived macrophage; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; BCL2L13: BCL2-like 13 (apoptosis facilitator); CCCP: carbonyl cyanide m-cholorophenyl hydrazone; FUNDC1: FUN14 domain-containing 1; FKBP8: FKBP506 binding protein 8; HCV: hepatitis C virus; HBV: hepatitis B virus; IFN: interferon; L. monocytogenes: Listeria monocytogenes; M. bovis: Mycobacterium bovis; Mtb: Mycobacterium tuberculosis; Mdivi-1: mitochondrial division inhibitor 1; PINK1: PTEN-induced putative kinase 1; TBK1: TANK-binding kinase 1; TUFM: Tu translation elongation factor, mitochondrial; TEM: transmission electron microscopy.

Keywords: Macrophage; Mycobacterium bovis; mitophagy; p-TBK1; xenophagy.

Publication types

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

MeSH terms

Animals
Macroautophagy*
Macrophages* / microbiology
Membrane Proteins
Mice
Mitochondrial Proteins / metabolism
Mitophagy*
Mycobacterium bovis* / metabolism

Substances

Membrane Proteins
Mitochondrial Proteins

Grants and funding

This work was supported by the National Natural Science Foundation of China [32172800, 31873005]; High-end Foreign Experts Recruitment Program [GDW20151100036, GDW20161100071]; MoSTRCUK international cooperation project [2013DFG32500]; China Agriculture Research System [CARS-36]; National Key Research and Development Program [2017YFD0500901].