RESUMEN
Despite substantial investment and effort by federal agencies and institutions to improve the diversity of the professoriate, progress is excruciatingly slow. One program that aims to enhance faculty diversity is the Institutional Research and Academic Career Development Award (IRACDA) funded by the National Institutes of Health/National Institute of General Medical Sciences. IRACDA supports the training of a diverse cohort of postdoctoral scholars who will seek academic research and teaching careers. The San Diego IRACDA program has trained 109 postdoctoral scholars since its inception in 2003; 59% are women and 63% are underrepresented (UR) Black/African-American, Latinx/Mexican-American, and Indigenous scientists. Sixty-four percent obtained tenure-track faculty positions, including a substantial 32% at research-intensive institutions. However, the COVID-19 pandemic crisis threatens to upend IRACDA efforts to improve faculty diversity, and academia is at risk of losing a generation of diverse, talented scholars. Here, a group of San Diego IRACDA postdoctoral scholars reflects on these issues and discusses recommendations to enhance the retention of UR scientists to avoid a "lost generation" of promising UR faculty scholars.
Asunto(s)
COVID-19 , Diversidad Cultural , Educación de Postgrado , Docentes Médicos/estadística & datos numéricos , Becas/estadística & datos numéricos , Pandemias , SARS-CoV-2 , Universidades/estadística & datos numéricos , California , Educación de Postgrado/economía , Etnicidad/estadística & datos numéricos , Docentes Médicos/economía , Femenino , Humanos , Masculino , Grupos Minoritarios/estadística & datos numéricos , National Institute of General Medical Sciences (U.S.) , National Institutes of Health (U.S.) , Investigadores/economía , Investigadores/educación , Investigadores/estadística & datos numéricos , Salarios y Beneficios/estadística & datos numéricos , Estados Unidos , Universidades/economía , Mujeres/educaciónRESUMEN
Inflammatory cell death, or pyroptosis, is triggered by pathogenic infections or events. It is executed by caspase-1 (in the canonical pyroptosis pathway) or caspase-11 (noncanonical pathway), each via production of a cell-lytic domain from the pyroptosis effector protein gasdermin D through specific and limited proteolysis. Pyroptosis is accompanied by the release of inflammatory mediators, including the proteolytically processed forms of interleukin-1ß (IL-1ß) and IL-18. Given the similar inflammatory outcomes of the canonical and noncanonical pyroptosis pathways, we hypothesized that caspase-1 and -11 should have very similar activities and substrate specificities. To test this hypothesis, we purified recombinant murine caspases and analyzed their primary specificities by massive hybrid combinatorial substrate library (HyCoSuL) screens. We correlated the substrate preferences of each caspase with their activities on the recombinant natural substrates IL-1ß, IL-18, and gasdermin D. Although we identified highly selective and robust peptidyl substrates for caspase-1, we were unable to do so for caspase-11, because caspase-1 cleaved even the best caspase-11 substrates equally well. Caspase-1 rapidly processed pro-IL-1ß and -18, but caspase-11 processed these two pro-ILs extremely poorly. However, both caspase-1 and -11 efficiently produced the cell-lytic domain from the gasdermin D precursor. We hypothesize that caspase-11 may have evolved a specific exosite to selectively engage pyroptosis without directly activating pro-IL-1ß or -18. In summary, comparing the activities of caspase-1 and -11 in HyCoSuL screens and with three endogenous protein substrates, we conclude that caspase-11 has highly restricted substrate specificity, preferring gasdermin D over all other substrates examined.
Asunto(s)
Caspasa 1/metabolismo , Caspasas/metabolismo , Péptidos/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Caspasas Iniciadoras , Muerte Celular , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Ratones , Proteínas de Unión a Fosfato , Proteolisis , Proteínas Recombinantes/metabolismo , Especificidad por SustratoRESUMEN
Caspases belong to a diverse clan of proteolytic enzymes known as clan CD with highly disparate functions in cell signaling. The caspase members of this clan are only found in animals, and most of them orchestrate the demise of cells by the highly distinct regulated cell death phenotypes known as apoptosis and pyroptosis. This review looks at the mechanistic distinctions between the activity and activation mechanisms of mammalian caspases compared to other members of clan CD. We also compare and contrast the role of different caspase family members that program anti-inflammatory and pro-inflammatory cell death pathways.