PEX19 restricts porcine deltacoronavirus replication through farnesylation-dependent and -independent mechanisms.

Peroxisomes are vital cellular organelles that play critical roles in metabolism, immune regulation, and disease pathogenesis. As a key receptor for peroxisomal membrane proteins, peroxisomal biogenesis factor 19 (PEX19) is essential for peroxisome biogenesis. In this study, we identify PEX19 as a novel host restriction factor against porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential. Overexpression of PEX19 significantly inhibits PDCoV replication, while knockout of PEX19 enhances viral propagation. Interestingly, the anti-PDCoV effect of PEX19 largely depends on its farnesylation modification, as PEX19 mutants with deleted or mutated farnesylation sites exhibit only marginal anti-PDCoV activity. Mechanistically, PEX19 restricts PDCoV infection through three distinct pathways: (i) reducing cellular cholesterol levels in a farnesylation-dependent manner, (ii) targeting the viral nonstructural protein 2 (nsp2) for autophagy-lysosome-mediated degradation, which is also dependent on farnesylation, and (iii) inducing low-level interferon production independently of farnesylation. Taken together, these findings define a new antiviral role for PEX19 and highlight its potential as a therapeutic target for combating PDCoV infection.IMPORTANCEPeroxisomes are increasingly recognized as critical regulators of virus-host interactions; however, their roles during coronavirus infection remain poorly understood and controversial. By screening the peroxins (PEXs) that regulate the replication of porcine deltacoronavirus (PDCoV), we identify PEX19, a key peroxisomal biogenesis factor, as a novel antiviral host protein, whose anti-PDCoV activity is largely dependent on farnesylation modification. Our findings demonstrate that farnesylated PEX19 restricts PDCoV replication by reducing cellular cholesterol levels and promoting autophagy-lysosome-mediated degradation of the viral nsp2 protein, while also inducing low-level interferon production independently of farnesylation. These results provide new molecular insights into PDCoV-host interactions and highlight PEX19 as a potential therapeutic target against PDCoV infection.