ABSTRACT Serine incorporator 5 (SERINC5) restricts the infectivity of various enveloped viruses, including HIV‐1 and severe acute respiratory syndrome coronavirus 2. However, these pandemic viral pathogens have evolved mechanisms to counteract this restriction. Here, we examined the impact of all five human SERINC family members on the seasonal human coronaviruses (hCoVs) 229E and OC43, which account for up to 15% of global mild respiratory infections and can cause severe disease in vulnerable individuals. Our data show that both exogenous and endogenous SERINC1, SERINC3, and SERINC5 significantly reduce OC43 infectivity in human lung and liver cells but have little, if any, effect on 229E. Functional analyses revealed that both the 130‐amino‐acid ORF4a protein encoded by most laboratory 229E strains and the full‐length 219 amino acid ORF4 protein encoded by clinical 229E isolates antagonize SERINC5 by promoting its relocalization to lysosomes and subsequent degradation. Finally, we show that endogenous SERINC5 expression in primary human lung cells inhibits infection by ORF4‐deficient but not wild‐type hCoV‐229E. In conclusion, several SERINC proteins restrict hCoV‐OC43, whereas hCoV‐229E efficiently counteracts SERINC‐mediated restriction by its ORF4/4a accessory proteins to ensure efficient production of fully infectious viral particles.
Xie et al. (2026) studied this question.