卞兆祥、陈烨等:自噬调控因子NRBF2促进清除凋亡细胞,抑制肠道炎症
创作:aluba 审核:aluba 2020年07月21日
  • NRBF2的缺失恶化DSS诱导的小鼠结肠炎,促进凋亡细胞累积;
  • 缺失NRBF2抑制巨噬细胞对凋亡细胞的清除,将NRBF2阳性巨噬细胞过继转移给NRBF2缺陷小鼠可缓解DSS诱导的结肠炎;
  • NRBF2对于RAB7+ 晚期吞噬体形成是必需的,以促进含有凋亡细胞的吞噬体与溶酶体的融合;
  • 在UC患者的结肠活检样本中,结肠巨噬细胞中的NRBF2上调,并可观察到NRBF2阳性细胞对凋亡细胞的吞噬;
  • 活动性UC患者的疾病严重程度与结肠活检样本中的凋亡细胞累积呈正相关。
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aluba
NRBF2是ATG14-BECN1/Beclin 1-PIK3C3/VPS34复合物中的一个调节亚基,对自噬有正向调控作用。近期,澳门大学路嘉宏、香港浸会大学卞兆祥和李敏、南方医科大学南方医院陈烨作为共同通讯作者在Autophagy上发表的一项研究发现,缺失NRBF2可抑制巨噬细胞对凋亡细胞的清除,以恶化DSS诱导的小鼠结肠炎。在溃疡性结肠炎(UC)患者的结肠活检样本中,巨噬细胞的NRBF2表达上调,而凋亡细胞的累积与疾病严重程度显著正相关。该研究结果揭示,NRBF2通过促进巨噬细胞对凋亡细胞的吞噬与清除,在肠道炎症中起到保护性作用。
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Autophagy [IF:16.016]

PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation

PIK3C3亚基NRBF2对于清除凋亡细胞以抑制肠道炎症是必需的

10.1080/15548627.2020.1741332

2020-05-19, Article

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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.

First Authors:
Ming-Yue Wu

Correspondence Authors:
Min Li,Ye Chen,Zhao-Xiang Bian,JiaHong Lu

All Authors:
Ming-Yue Wu,Le Liu,Er-Jin Wang,Hai-Tao Xiao,Cui-Zan Cai,Jing Wang,Huanxing Su,Yitao Wang,Jieqiong Tan,Zhuohua Zhang,Juan Wang,Maojing,Yao,De-Fang Ouyang,Zhenyu Yue,Min Li,Ye Chen,Zhao-Xiang Bian,JiaHong Lu

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