WDFY4 Is Involved in Symptoms of Systemic Lupus Erythematosus by Modulating B Cell Fate via Noncanonical Autophagy
WDFY4 Is Involved in Symptoms of Systemic Lupus Erythematosus by Modulating B Cell Fate via Noncanonical Autophagy
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WDFY4 通过非典型自噬调节 B 细胞命运，从而参与系统性红斑狼疮的症状
DOI：
10.4049/jimmunol.1800399
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发表时间：
2018-11-01
影响因子：
4.4
通讯作者：
Liu, Qiji
中科院分区：
文献类型：
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作者：
Yuan, Qianqian;Li, Yan;Liu, Qiji
最近的全基因组关联研究表明，WDFY4与不同种族的系统性红斑狼疮(SLE)易感性存在遗传关联。尽管强有力的遗传学证据表明WDFY4在SLE发病机制中发挥作用，但其功能相关性在很大程度上尚不清楚。在本研究中，我们建立了Wdfy4 B淋巴细胞条件性基因敲除(Wdfy4-CKO)小鼠，发现Wdfy4基因的缺失导致B细胞总数和外周血中几个B细胞亚群的减少，并导致骨髓中从前B细胞阶段到前B细胞阶段的转换出现缺陷。此外，Wdfy4-CKO小鼠在接受抗原攻击时，与对照组相比，抗体反应受损。Wdfy4-CKO小鼠的SLE表型得到有效缓解，Pristane诱导的自身抗体和肾小球肾炎的产生显著减少。WDFY4在B细胞中的遗传沉默增加了Lc3的脂化，而不依赖于p62和Beclin1，这两个蛋白是典型自噬的关键蛋白。我们的体内和体外数据表明，WDFY4促进了非典型的自噬活性。我们的发现为系统性红斑狼疮的发病机制提供了一个新的功能联系，即WDFY4通过非典型自噬影响B细胞的命运。
Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout (Wdfy4-CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4-CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4-CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.