RESUMEN
Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the Caenorhabditis elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here, we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress signaling from the intestine to the muscle is regulated. We find that the TCS-mediated "gut-to-muscle" induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of "inter-tissue" stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated heat shock response is switched off upon TCS activation, in favor of an intercellular stress-signaling route to safeguard survival.
Asunto(s)
Proteínas de Caenorhabditis elegans , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Factores de Transcripción/metabolismo , Transducción de Señal , Factores de Transcripción del Choque Térmico/metabolismo , Respuesta al Choque Térmico/genética , Caenorhabditis elegans/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismoRESUMEN
Human coronavirus OC43 is a globally circulating common cold virus sustained by recurrent reinfections. How it persists in the population and defies existing herd immunity is unknown. Here we focus on viral glycoprotein S, the target for neutralizing antibodies, and provide an in-depth analysis of its antigenic structure. Neutralizing antibodies are directed to the sialoglycan-receptor binding site in S1A domain, but, remarkably, also to S1B. The latter block infection yet do not prevent sialoglycan binding. While two distinct neutralizing S1B epitopes are readily accessible in the prefusion S trimer, other sites are occluded such that their accessibility must be subject to conformational changes in S during cell-entry. While non-neutralizing antibodies were broadly reactive against a collection of natural OC43 variants, neutralizing antibodies generally displayed restricted binding breadth. Our data provide a structure-based understanding of protective immunity and adaptive evolution for this endemic coronavirus which emerged in humans long before SARS-CoV-2.