ArticleJournal of virology2025
Phosphorylation of Shiftless by casein kinase 1 δ/ε is required for its antiviral activity.
Article in Journal of virology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Shiftless (SHFL) is a host antiviral factor that inhibits the viral -1 programmed ribosomal frameshifting (-1PRF). How the antiviral activity of SHFL is regulated is not known. Here, we report that the phosphorylation of SHFL by the casein kinase 1 delta (CK1δ) and epsilon (CK1ε) regulates its antiviral activity. The casein kinases were identified as SHFL-interacting proteins. Downregulation of the expression of the endogenous casein kinases or pharmacological inhibition of kinase activity significantly impaired the activity of SHFL to inhibit HIV-1 -1PRF and viral production. The residues T250 and T253 were identified as critical phosphorylation sites; substitution of either of the residues with alanine, resulting in the mutants SHFL-T250A or SHFL-T253A, abolished the antiviral activity of SHFL against HIV-1. The T250A mutation did not affect SHFL interaction with target RNA or the ribosomal proteins uL5 and eS31 but significantly reduced its interaction with IGF2BP proteins. Furthermore, SHFL-T250A displayed reduced association with the actively translating polysomes. These results are consistent with the notion that SHFL interaction with ribosomes is critical for its activity to inhibit -1PRF. Taken together, our results indicate that phosphorylation of SHFL by CK1δ/ε is required for its antiviral activity.IMPORTANCEInnate immune responses and antiviral defense mechanisms are regulated through a variety of mechanisms, among which post-translational modifications, especially phosphorylation, play important roles. Deciphering the regulatory mechanisms helps understand the innate immune responses more comprehensively. SHFL is an interferon-stimulated host antiviral factor that inhibits the replication of multiple viruses. The present study revealed that phosphorylation of SHFL by casein kinase 1 δ/ε is required for its antiviral activity against HIV-1. These results provide an additional example for how immune responses are regulated. Furthermore, given that SHFL inhibits -1PRF, the present studies provide tools for further exploring the mechanisms of -1PRF.
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