The diverse functions of viral microproteins

The uncharacterized proteome contains a significant portion of microproteins, which are particularly abundant in viruses. These microproteins exhibit potent activities, making them valuable for studying their functions and evolution. Researchers have now developed a systematic method to annotate these viral microproteins by creating a library of 50,000 small open reading frames (ORFs) from human-infecting viruses.

This library was then subjected to broad screens, enabling the enrichment of candidates for detailed analysis through techniques such as Perturb-seq, mass spectrometry, AI-guided structure prediction, and mechanistic studies.

The efforts led to the identification of approximately 2,000 active microproteins that manipulate host pathways through various mechanisms. These include molecular mimicry, commandeering of essential regulators, and modifications to subcellular localization. One notable example is the oncogenic microprotein BNLF2b, an uncharacterized protein found in the Epstein-Barr virus, which is associated with nasopharyngeal carcinoma.

The study reveals three key principles about viral microproteins. Firstly, they are diverse and often multifunctional, performing numerous roles simultaneously. Secondly, these microproteins show widespread convergence in their functions, suggesting a common evolutionary origin. Lastly, they serve as reservoirs of evolutionary innovation, contributing to the adaptability and resilience of viruses.

This comprehensive annotation of viral microproteins not only elucidates their extensive functional landscape but also highlights their versatility as tools for manipulating host processes. It also provides a framework for annotating uncharacterized proteins, advancing the field of predictive systems virology.