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The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells [CLIP-seq and mRNA-seq]

ABSTRACT: The integrated stress response (ISR) suppresses global translation while allowing the selective translation of key regulatory genes. However, the mechanisms behind sustained protein synthesis during ISR activation remain unclear. In eukaryotic cells, the 5′-cap of most mRNAs is bound either by the nuclear cap-binding complex (CBC) or by the cytosolic cap-binding protein eIF4E. Our study reveals that under stress conditions, CBC-bound mRNAs utilize eIF2A, an alternative translation initiation factor, to maintain protein synthesis when translation of eIF4E-bound mRNAs is significantly inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue active proliferation due to a compensatory increase in eIF2A expression. This increase ensures CBC-dependent translation (CT) and supports the synthesis of essential cell cycle proteins during stress. Furthermore, we identify YAP, a master regulator of cell proliferation, as a critical target of CT, driving stress-resistant proliferation in stem cells. Collectively, our findings highlight CT as a crucial pathway that protects protein synthesis and supports stem cell proliferation during stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291613 | GEO | 2026/03/30

REPOSITORIES: GEO

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Project description:Virus infection may shut off host protein synthesis in order to achieve the replicative advantage over host cells. It is well known that human pathogenic viruses, particularly the picornaviruses, can block host protein synthesis by cleavage or inhibition of eukaryotic initiation factors (eIFs). In this study we found a novel mechanism that microRNA (miRNA) is involved in viral pathogenesis. Infection of enteroviruses can disturb the expression of host miRNAs, in which miR-141 is up-regulated and inhibits host protein synthesis by post-transcriptional repression of the target gene eIF4E, a key element for cap-dependent translation of host proteins. Knockdown of miR-141 by a specific siRNA, antagomiR-141, could restore host eIF4E expression, delay the occurrence of cytopathic effect (CPE), and impair virus propagation. We demonstrated that EV71 infection could increase early growth response 1 (EGR1) expression which induced miR-141 causing the eIF4E suppression; while silencing of EGR1 attenuated virus production. Our results suggest that enterovirus infection causes the EGR1-mediated upregulation of host miR-141, further lead to the translational switch from cap-dependent to cap-independent protein synthesis in the host cells, an environmental beneficial for viral propagation. This novel mechanism may highlight a new approach for future development of antiviral therapy. Enteroviruses in the Picornaviridae family are important human pathogens which can cause fatal diseases, including cardiopulmonary failure, aseptic meningitis, paralysis, myocarditis, and encephalomyelitis. Virus infection may induce shutoff of host protein synthesis, particularly in picornavirus, whose protein translation is cap-independent. It is known that poliovirus 2A protease cleaves eIF4G, a scaffold component of mammalian cell translational complex, leading to the shut down of host protein synthesis. Nevertheless, the cleavage of eIF4G may not be sufficient for the complete shutoff of host protein synthesis. Previous studies showed that cleavage of polyA-binding protein (PABP) by viral protease 3C and dephosphorylation of the translational repressor, eIF4E binding protein 1 (4E-BP1), also contribute to this process. The cap-binding protein, eIF4E, is the most crucial factor in determining whether cap-dependent or -independent translation takes place. The mechanism by which viral infection modulates host cell protein synthesis through interfering eIF4E expression is not yet known. miRNAs are a newly discovered class of small non-protein-coding RNAs that may act via endogenous RNA interference. Our understanding of its role in the dynamic interplay between virus and host components is quite limited. Since both virus infection and miRNAs could hinder cellular protein synthesis, whether miRNAs are involved during virus infection in shutting off host protein synthesis is still unknown. To address this issue, we analyze the altered gene and microRNA expression after EV71 infection. ***This submission represents the mRNA expression component of the study only***

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The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells [CLIP-seq and mRNA-seq]

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