ALDH1L1 suppresses the replication of porcine epidemic diarrhea virus by degrading viral nucleocapsid and envelope proteins

ABSTRACT Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic alphacoronavirus that causes severe diarrhea. It has a high fatality rate among newborn piglets, posing a considerable economic burden to the swine industry. Therefore, elucidating the host–pathogen interaction is warranted to advance precision antiviral therapies. Herein, for the first time, we noted a marked upregulation of aldehyde dehydrogenase 1 family member L1 (ALDH1L1) during PEDV infection. Furthermore, ALDH1L1 exerts its antiviral effects by specifically binding to the viral nucleocapsid (N) and envelope (E) proteins and mediating their degradation via the autophagosome–lysosomal degradation pathway. Additional experiments revealed that this degradation process is mediated via the interactions of ALDH1L1 with the E3 ubiquitin ligase STUB1 and the cargo receptor TOLLIP, eliminating the N and E structural glycoproteins via the autophagolysosomal pathway. Our study findings suggest the ALDH1L1-STUB1-TOLLIP axis as a novel antiviral target and propose a new strategy for viral clearance based on the degradation of host protein. Furthermore, our research provides valuable information on how host antiviral factors impede PEDV replication as a regulator of the protein degradation pathway. IMPORTANCE Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic alphacoronavirus that causes fatal hemorrhagic gastroenteritis among neonatal piglets. This causes significant financial losses. During infection, certain host factors can activate the innate immune regulatory network to antagonize the viral replication cycle, interfere with the virus invasion, inhibit virus replication, prevent virus assembly and release, and enhance the host’s immune response. Our study revealed that the host metabolic enzyme ALDH1L1 acts as a novel antiviral restriction factor that mediates the autophagy–lysosome–targeted degradation of viral structural proteins (N/E) via the STUB1 (E3 ubiquitin ligase)–TOLLIP (autophagy adaptor protein) axis. Our study findings offer new perspectives on the mechanism by which host antiviral factors inhibit PEDV by regulating the protein degradation pathway.