机会性致病菌靶向LC3B-神经酰胺复合物并介导口腔肿瘤中的致死性线粒体自噬抗性。

Opportunistic pathogen targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors.

作者信息

Sheridan Megan, Chowdhury Nityananda, Wellslager Bridgette, Oleinik Natalia, Kassir Mohamed Faisal, Lee Han G, Engevik Mindy, Peterson Yuri, Pandruvada Subramanya, Szulc Zdzislaw M, Yilmaz Özlem, Ogretmen Besim

机构信息

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.

Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.

出版信息

iScience. 2024 Apr 30;27(6):109860. doi: 10.1016/j.isci.2024.109860. eCollection 2024 Jun 21.

DOI:10.1016/j.isci.2024.109860

PMID:38779482

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11108982/

Abstract

Mechanisms by which () infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type prevented ceramide-dependent mitophagy. Moreover, a FimA-deletion mutant variant had no inhibitory effects on ceramide-dependent mitophagy. Further, 16S rRNA sequencing of oral tumors indicated that infection altered the microbiome of the tumor macroenvironment in response to ceramide analog treatment in mice. Thus, these data provide a mechanism describing the pro-survival roles of in oral tumors.

摘要

（）感染增强口腔肿瘤生长或对细胞死亡的抗性的机制仍不清楚。在这里，我们确定感染通过抑制癌细胞和肿瘤中的致死性线粒体自噬来介导治疗抗性。从机制上讲，通过细菌主要菌毛（FimA）蛋白与LC3B结合来靶向LC3B-神经酰胺复合物，从而在响应各种治疗剂时阻止神经酰胺依赖性线粒体自噬。此外，膜联蛋白A2（ANXA2）-神经酰胺结合涉及ANXA2的E142残基，从而诱导神经酰胺介导的线粒体自噬。野生型对ANXA2-神经酰胺-LC3B复合物形成的抑制阻止了神经酰胺依赖性线粒体自噬。此外，FimA缺失突变体变体对神经酰胺依赖性线粒体自噬没有抑制作用。此外，口腔肿瘤的16S rRNA测序表明，感染会响应小鼠体内神经酰胺类似物治疗而改变肿瘤宏观环境的微生物群。因此，这些数据提供了一种机制，描述了在口腔肿瘤中的促生存作用。