RESUMEN
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.
Asunto(s)
Proteínas Bacterianas , Burkholderia pseudomallei , Macrófagos , Mitocondrias , Mitofagia , Burkholderia pseudomallei/metabolismo , Burkholderia pseudomallei/patogenicidad , Burkholderia pseudomallei/fisiología , Burkholderia pseudomallei/genética , Animales , Ratones , Mitocondrias/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Humanos , Macrófagos/microbiología , Macrófagos/metabolismo , Ubiquitinación , Melioidosis/microbiología , Melioidosis/metabolismo , Interacciones Huésped-Patógeno , Especies Reactivas de Oxígeno/metabolismo , Sistemas de Secreción Tipo III/metabolismo , Sistemas de Secreción Tipo III/genética , Ratones Endogámicos C57BL , Membranas Mitocondriales/metabolismo , Células HEK293 , Células RAW 264.7RESUMEN
Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in bidirectional crosstalk between pancreatic tumor epithelium and TME and results in a pro-|tumorigenic contexture.