Research

Discrete and overlapping functions of YBXs during cellular homeostasis and RNA virus infection. During cellular homeostasis, YBX1 and YBX3 bind various non-coding RNAs (including miRNAs, Y RNAs, and tRNAs), some of which are known to be associated with autoimmune diseases. YBX1 and YBX3 also bind cytoplasmic mt-tRNAs that are released via mitophagy. YBX1 aids in the shuttling of mitochondrial resident miR-223 into extracellular vesicles, potentially utilizing cellular phase-separated condensates like P-bodies as nucleating points before multivesicular body (MVB) formation and secretion. We hypothesize that YBXs shield immunogenic moieties on cellular non-coding RNAs, including dsRNA regions and 5’-triphosphates, preventing their recognition by cytoplasmic RLRs and TLRs, to prevent the aberrant induction of inflammation (depicted by dashed lines). Alternatively, YBXs may participate in the turnover of cellular non-coding RNAs via their secretion in extracellular vesicles or degradation by MVBs fusing with lysosomes (depicted by dashed lines). YBX1 and YBX2 also form phase-separated condensates, and YBX1 phase-separated condensates co-localize with p-body markers such as DDX6. The global deposition of m5C on RNA by the m5C writer NSUN2 positively affects YBX2’s ability to form phase-separated condensates. YBX1 and YBX2 are both m5C readers and promote the association of other cellular RBPs with m5C-modified RNAs, increasing their stability. Globally, all three human YBXs promote the stability of cellular mRNAs, from post-meiotic germ cells to somatic cells. During infection, YBX1 also stabilizes viral RNA via recognition of an m5C modification on the HCV genome. During infection with Retroviridae, YBX1 both promotes and represses the transcription of HTLV-1, through dynamic association with viral proteins. During infection with Flaviviridae, YBX1 balances HCV replication and virion release, and promotes DENV-2 virion assembly. Across multiple Togaviridae, YBX1 is necessary for efficient viral RNA replication. Lastly, during Orthomyxoviriade infection, YBX1 and YBX3 have opposing anti- and pro-viral functions: YBX3 represses transcription of IAV while YBX1 promotes IAV RNP egress via endosomes. (PMID 40985650)

All viral genomes converge in the generation of a mRNA. Viral genomes are classified into seven classes (I-VII) based on their replication strategies and their mechanisms of mRNA synthesis. *mRNA is represented here containing a 5′-cap and a 3′-poly-adenylated tail, which is true for most cellular mRNAs, but not all viral mRNAs. Created in BioRender. Fernandez, L. (2024) https://BioRender.com/h31e575.  From ref PMID 40089163.