Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

• Published in: Nature communications Vol. 15; no. 1; pp. 4740 - 17
• Main Authors: Nan, Dongqi, Rao, Chenglong, Tang, Zhiheng, Yang, Wenbo, Wu, Pan, Chen, Jiangao, Xia, Yupei, Yan, Jingmin, Liu, Wenzheng, Zhang, Ziyuan, Hu, Zhiqiang, Chen, Hai, Liao, Yaling, Mao, Xuhu, Liu, Xiaoyun, Zou, Quanming, Li, Qian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/31; 13/89; 14/19; 14/28; 14/34; 14/35; 631/250/2161; 631/326/421; 631/326/88; 64/60; 82/1; 82/29; 82/58; 82/83; Animals; Autophagy; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Burkholderia pseudomallei; Burkholderia pseudomallei - genetics; Burkholderia pseudomallei - metabolism; Burkholderia pseudomallei - pathogenicity; Burkholderia pseudomallei - physiology; HEK293 Cells; Homeostasis; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Infectious diseases; Macrophages; Macrophages - metabolism; Macrophages - microbiology; Melioidosis - metabolism; Melioidosis - microbiology; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitochondrial Membranes - metabolism; Mitophagy; multidisciplinary; Proteins; Quality control; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Substrates; Survival; Type III Secretion Systems - genetics; Type III Secretion Systems - metabolism; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48824-x

Mitophagy is critical for mitochondrial quality control and function to clear damaged mitochondria. Here, we found that Burkholderia pseudomallei maneuvered host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD. We identified BipD, interacting with BTB-containing proteins KLHL9 and KLHL13 by binding to the Back and Kelch domains, recruited NEDD8 family RING E3 ligase CUL3 in response to B. pseudomallei infection. Although evidently not involved in regulation of infectious diseases, KLHL9/KLHL13/CUL3 E3 ligase complex was essential for BipD-dependent ubiquitination of mitochondria in mouse macrophages. Mechanistically, we discovered the inner mitochondrial membrane IMMT via host ubiquitome profiling as a substrate of KLHL9/KLHL13/CUL3 complex. Notably, K63-linked ubiquitination of IMMT K211 was required for initiating host mitophagy, thereby reducing mitochondrial ROS production. Here, we show a unique mechanism used by bacterial pathogens that hijacks host mitophagy for their survival. The selective degradation of mitochondria by autophagy is essential for cell homeostasis. Here, Nan et al show that the effector protein BipD, secreted by Burkholderia pseudomallei , is able to modulate host mitophagy to promote its survival.