ULBP5 mediates the pathogenesis of Henoch-Schönlein Purpura by modulating endothelial cell proliferation and migration.

ULBP5, a member of the ULBP family, interacts with the NKG2D receptor on natural killer (NK) cells. Despite this, the specific roles of ULBP5 in NK cell activation and its overall function remain poorly defined. Our study found mutations in the ULBP5 gene in 3 familial cases of Henoch-Schönlein Purpura (HSP) and in 9 out of 123 sporadic HSP patients. We demonstrate that ULBP5-mutation is a risk factor for the development of HSP. We utilized protein prediction software and discovered that certain ULBP5 mutations impact ULBP5 protein structure and function. To explore the cellular and molecular mechanisms involved, we created models of human renal glomerular endothelial cells (HRGECs) with ULBP5 mutations, ULBP5 knockdown (ULBP5-KD), and ULBP5 overexpression (ULBP5-OE). We found that specific mutations can impair the proliferative and self-protective capacities of HRGECs, increasing their vulnerability to immune-mediated damage. ULBP5-KD reduced angiogenesis, proliferation, and migration in HRGECs, potentially linked to decreased ERK phosphorylation. Additionally, ULBP5-KD made HRGECs more susceptible to NK cell-induced damage and seemed to enhance NK cell activation. Mechanistic studies, including RNA sequencing and validation experiments, indicated that ULBP5-KD promotes apoptosis and ferroptosis in HRGECs. Co-culturing ULBP5-KD HRGECs with NK cells led to elevated inflammatory factor secretion, possibly enhancing NK cell recruitment and exacerbating damage. These findings suggest similarities between the effects of certain ULBP5 mutations and ULBP5-KD, providing significant insights into the molecular mechanisms of HSP and the impact of ULBP5 deficiency on HRGEC function.