Proteomics of autophagy deficient macrophages reveals enhanced antimicrobial immunity via the oxidative stress response
Proteomics of autophagy deficient macrophages reveals enhanced antimicrobial immunity via the oxidative stress response
Abstract Defective autophagy is associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohn’s disease by enhancing innate immunity in macrophages. However, autophagy also mediates clearance of intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in antimicrobial immunity. In this study, we found that loss of Atg16l1 in macrophages enhanced the killing of virulent Shigella flexneri (S.flexneri), an enteric bacterium that resides within the cytosol by escaping all membrane-bound compartments. Quantitative multiplexed proteomics revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which also promoted S.flexneri killing. Consistently, myeloid cell-specific deletion of Atg16l1 accelerated bacterial clearance in vivo. Finally, pharmacological modulation of oxidative stress by suppression of cysteine import conferred enhanced microbicidal properties to wild type macrophages. These findings demonstrate that control of oxidative stress by ATG16L1 regulates antimicrobial immunity against intracellular pathogens. Impact statementMaculins et al utilize multiplexed mass spectrometry to show that loss of the autophagy gene Atg16l1 in macrophages enhances antimicrobial immunity against intracellular pathogens via the oxidative stress response.
Erickson Brian K.、Vitek Olga、Reichelt Mike、Rohde John、Dikic Ivan、Murthy Aditya、Chang Patrick、Kunz Ryan C.、Katakam Anand Kumar、Choi Meena、Kirkpatrick Donald S.、Hinkle Trent、Verschueren Erik、Tsai Tsung-Heng、Huang Ting、Chalouni Cecile、Lim Junghyun、Maculins Timurs
IQ Proteomics LLCKhoury College of Computer Sciences, Northeastern UniversityDepartment of Pathology, GenentechDepartment of Microbiology and Immunology, Dalhousie UniversityDepartment of Infectious Diseases, Genentech||Institute of Biochemistry II, Goethe UniversityDepartment of Cancer Immunology, GenentechDepartment of Pathology, GenentechIQ Proteomics LLCDepartment of Pathology, GenentechKhoury College of Computer Sciences, Northeastern UniversityDepartment of Microchemistry, Proteomics and Lipidomics, GenentechDepartment of Microchemistry, Proteomics and Lipidomics, GenentechDepartment of Microchemistry, Proteomics and Lipidomics, GenentechKhoury College of Computer Sciences, Northeastern University||Department of Mathematical Sciences, Kent State UniversityKhoury College of Computer Sciences, Northeastern UniversityDepartment of Pathology, GenentechDepartment of Cancer Immunology, GenentechDepartment of Cancer Immunology, Genentech||Institute of Biochemistry II, Goethe University
基础医学生物科学研究方法、生物科学研究技术分子生物学
Erickson Brian K.,Vitek Olga,Reichelt Mike,Rohde John,Dikic Ivan,Murthy Aditya,Chang Patrick,Kunz Ryan C.,Katakam Anand Kumar,Choi Meena,Kirkpatrick Donald S.,Hinkle Trent,Verschueren Erik,Tsai Tsung-Heng,Huang Ting,Chalouni Cecile,Lim Junghyun,Maculins Timurs.Proteomics of autophagy deficient macrophages reveals enhanced antimicrobial immunity via the oxidative stress response[EB/OL].(2025-03-28)[2025-06-25].https://www.biorxiv.org/content/10.1101/2020.09.10.291344.点此复制
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