Calmodulin-like 5 promotes PEDV replication by regulating late-endosome synthesis and innate immune response

• Published in: Virologica Sinica 2024-06, Vol.39 (3), p.501-512
• Main Authors: Tian, Wen-Jun, Zhang, Xiu-Zhong, Wang, Jing, Liu, Jian-Feng, Li, Fu-Huang, Wang, Xiao-Jia
• Format: Article
• Language: English
• Subjects: Acidification; Antibodies; Calmodulin; Coronaviruses; Diarrhea; EF-hand; EF-hand protein calmodulin-like 5 (CALML5); Endosomes; Genes; Hand protein; Immune response; Infections; Innate immune response; Innate immunity; Late endosomes; mRNA; Phosphorylation; Porcine epidemic diarrhea virus (PEDV); Proteins; Proteomics; Replication; Transmissible gastroenteritis; Vaccines; Viral infections; Viruses; β-Interferon
• ISSN: 1995-820X; 1674-0769; 1995-820X
• DOI: 10.1016/j.virs.2024.05.006

The infection caused by porcine epidemic diarrhea virus (PEDV) is associated with high mortality in piglets worldwide. Host factors involved in the efficient replication of PEDV, however, remain largely unknown. Our recent proteomic study in the virus-host interaction network revealed a significant increase in the accumulation of CALML5 (EF-hand protein calmodulin-like 5) following PEDV infection. A further study unveiled a biphasic increase of CALML5 in 2 and 12 ​h after viral infection. Similar trends were observed in the intestines of piglets in the early and late stages of the PEDV challenge. Moreover, CALML5 depletion reduced PEDV mRNA and protein levels, leading to a one-order-of-magnitude decrease in virus titer. At the early stage of PEDV infection, CALML5 affected the endosomal trafficking pathway by regulating the expression of endosomal sorting complex related cellular proteins. CALML5 depletion also suppressed IFN-β and IL-6 production in the PEDV-infected cells, thereby indicating its involvement in negatively regulating the innate immune response. Our study reveals the biological function of CALML5 in the virology field and offers new insights into the PEDV-host cell interaction. •PEDV infection increases the accumulation of CALML5 both in vivo and in vitro.•CALML5 promotes PEDV virion internalization to influence late-endosome synthesis by regulating ESCRT.•CALML5 suppresses the production of IFN-β by targeting RIG-I-MAVS pathway.