WDFY4 Is Involved in Symptoms of Systemic Lupus Erythematosus by Modulating B Cell Fate via Noncanonical Autophagy

Abstract

Genome-wide association studies have recently illuminated that <i>WDFY4</i> is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of <i>WDFY4</i> in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated <i>Wdfy4</i> B lymphocyte conditional knockout (<i>Wdfy4</i>-CKO) mice and found that loss of <i>Wdfy4</i> 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, <i>Wdfy4</i>-CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in <i>Wdfy4</i>-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.