Endoplasmic reticulum membrane complex 1 facilitates BK polyomavirus genotype III/IV replication for nephropathy

BK polyomavirus nephropathy (BKPyVN) remains a major cause of renal allograft dysfunction. However, the influence of viral genotype on disease progression and host-virus interactions is not fully understood. We examined kidney transplant recipients presenting with urinary decoy cells and categorized them into asymptomatic BKPyV viruria and biopsy-confirmed BKPyVN. Genotyping of the VP1 region revealed that all asymptomatic viruria cases were genotype I, whereas 70 % of BKPyVN cases were genotype III or IV. Proteomic profiling of renal tubular epithelial cells infected with patient-derived BKPyV isolates demonstrated genotype-specific upregulation of Endoplasmic Reticulum Membrane Complex 1 (EMC1). Both EMC1 mRNA and protein expression were markedly increased in cells infected with genotype III/IV viruses, but not in genotype I or uninfected controls. siRNA-mediated EMC1 knockdown reduced infection rates from >25 % to <2 % of genotype III/IV, confirming its critical role in viral replication. These findings indicate that EMC1 facilitates intracellular trafficking of nephropathogenic BKPyV genotypes III/IV and promotes viral persistence in renal tubular cells. By integrating clinical genotype distribution with molecular and functional analyses, this study provides mechanistic evidence that genotypic variation drives the differential pathogenicity of BKPyV in kidney transplantation. Moreover, EMC1 emerges as a potential therapeutic target to reduce BKPyVN-associated graft loss and to enhance understanding of host-virus dynamics in polyomavirus infections.