Current Perspectives on Functional Involvement of Micropeptides in Virus-Host Interactions

Micropeptides (miPEPs), encoded by short open reading frames (sORFs) within various genomic regions, have recently emerged as critical regulators of multiple biological processes. In particular, these small molecules are now increasingly being recognized for their role in modulating viral replication, pathogenesis, and host immune responses. Both host miPEPs and virus-derived miPEPs have been noted for their ability to regulate virus-host interactions through diversified mechanisms such as altering protein stability and modulating protein-protein interactions. Although thousands of sORFs have been annotated as having the potential to encode miPEPs, only a small number have been experimentally validated so far, with some directly linked to virus-host interactions and a small subset associated with immune modulation, indicating that the investigation of miPEPs is still in its infancy. The systematic identification, translational status assessment, in-depth characterization, and functional analysis of a substantial fraction of sORFs encoding miPEPs remain largely underexplored. Further studies are anticipated to uncover the intricate mechanisms underlying virus-host interactions, host immune modulation, and the broader biological functions of miPEPs. This article will review the emerging roles of miPEPs in virus-host interactions and host immunity, and discuss the challenges and future perspectives of miPEP studies.