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PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation
Wu,Ming Yue1; Liu,Le2; Wang,Er Jin1; Xiao,Hai Tao3,4; Cai,Cui Zan1; Wang,Jing1; Su,Huanxing1; Wang,Yitao1; Tan,Jieqiong5; Zhang,Zhuohua6; Wang,Juan2; Yao,Maojing7; Ouyang,De Fang1; Yue,Zhenyu8; Li,Min3; Chen,Ye2; Bian,Zhao Xiang3; Lu,Jia Hong1
2021-07
Source PublicationAutophagy
ISSN1554-8627
Volume17Issue:5Pages:1096-1111
Abstract

NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that nrbf2 mice and macrophages displayed impaired apoptotic cell clearance capability, while adoptive transfer of nrbf2 macrophages to nrbf2 mice alleviated DSS-induced colitis lesions. Mechanistically, NRBF2 is required for the generation of the active form of RAB7 to promote the fusion between phagosomes containing engulfed apoptotic cells and lysosomes via interacting with the MON1-CCZ1 complex and regulating the guanine nucleotide exchange factor (GEF) activity of the complex. Evidence from clinical samples further reveals the physiological role of NRBF2 in maintaining intestinal homeostasis. In biopsies of UC patient colon, we observed upregulated NRBF2 in the colon macrophages and the engulfment of apoptotic cells by NRBF2-positive cells, suggesting a potential protective role for NRBF2 in UC. To confirm the relationship between apoptotic cell clearance and IBD development, we compared TUNEL-stained cell counts in the UC with UC severity (Mayo Score) and observed a strong correlation between the two indexes, indicating that apoptotic cell population in colon tissue correlates with UC severity. The findings of our study reveal a novel role for NRBF2 in regulating apoptotic cell clearance to restrict intestinal inflammation. 

KeywordApoptotic Cell Clearance Inflammatory Bowel Disease Macrophage Mon1-ccz1 Nrbf2 Rab7
DOI10.1080/15548627.2020.1741332
URLView the original
Indexed BySCIE
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000524246300001
Scopus ID2-s2.0-85082310860
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Cited Times [WOS]:11   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLi,Min; Chen,Ye; Bian,Zhao Xiang; Lu,Jia Hong
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
2.Department of Gastroenterology,State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Gastroenterology,Nanfang Hospital,Southern Medical University,Guangzhou,China
3.School of Chinese Medicine,Hong Kong Baptist University,Hong Kong
4.School of Pharmacy,Shenzhen University,Shenzhen,China
5.Center for Medical Genetics,School of Life Science,Central South University,Changsha,China
6.Institute of Molecular Precision Medicine,Xiangya Hospital,Central South University,Changsha,China
7.State Key Laboratory of Oncology in South China,Sun Yat-sen University Cancer Center,Guangzhou,China
8.Department of Neurology and Neuroscience,Friedman Brain Institute,Icahn School of Medicine at Mount Sinai,New York,United States
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Wu,Ming Yue,Liu,Le,Wang,Er Jin,et al. PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation[J]. Autophagy,2021,17(5):1096-1111.
APA Wu,Ming Yue,Liu,Le,Wang,Er Jin,Xiao,Hai Tao,Cai,Cui Zan,Wang,Jing,Su,Huanxing,Wang,Yitao,Tan,Jieqiong,Zhang,Zhuohua,Wang,Juan,Yao,Maojing,Ouyang,De Fang,Yue,Zhenyu,Li,Min,Chen,Ye,Bian,Zhao Xiang,&Lu,Jia Hong.(2021).PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation.Autophagy,17(5),1096-1111.
MLA Wu,Ming Yue,et al."PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation".Autophagy 17.5(2021):1096-1111.
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