RESUMEN
Energy stress, characterized by the reduction of intracellular ATP, has been implicated in various diseases, including cancer. Here, we show that energy stress promotes the formation of P-bodies in a ubiquitin-dependent manner. Upon ATP depletion, the E3 ubiquitin ligase TRIM23 catalyzes lysine-63 (K63)-linked polyubiquitination of HCLS1-associated protein X-1 (HAX1). HAX1 ubiquitination triggers its liquidâliquid phase separation (LLPS) and contributes to P-bodies assembly induced by energy stress. Ubiquitinated HAX1 also interacts with the essential P-body proteins, DDX6 and LSM14A, promoting their condensation. Moreover, we find that this TRIM23/HAX1 pathway is critical for the inhibition of global protein synthesis under energy stress conditions. Furthermore, high HAX1 ubiquitination, and increased cytoplasmic localization of TRIM23 along with elevated HAX1 levels, promotes colorectal cancer (CRC)-cell proliferation and correlates with poor prognosis in CRC patients. Our data not only elucidate a ubiquitination-dependent LLPS mechanism in RNP granules induced by energy stress but also propose a promising target for CRC therapy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Lisina , Ubiquitinación , Humanos , Lisina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Estrés Fisiológico , Células HEK293 , Proliferación Celular , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Gránulos Citoplasmáticos/metabolismo , Proteínas de Unión al GTPRESUMEN
Carolacton, a naturally occurring MTHFD1 inhibitor, exhibits potent inhibitory activity against various RNA viruses including SARS-CoV-2. Herein, we present a concise total synthesis of carolacton, featuring the Krische allylation, Marshall coupling, NHK coupling, and RCM reaction as key elements. Additionally, we have synthesized three simplified carolacton analogues, one of which, namely, 14-demethyl-carolacton, exhibited notable antiviral activity. The present work paves the way for further exploration of the therapeutic potential of carolacton and its analogues.
Asunto(s)
Antivirales , Macrólidos , Macrólidos/farmacología , Antivirales/farmacologíaRESUMEN
INTRODUCTION: The purpose of this study was to analyze the current status, the research hot spots and frontiers of cognitive impairment (CI) on old adults from 2012 to 2022 based on Web of Science (WoS) and China National Knowledge Infrastructure (CNKI) via CiteSpace, and provide new in-sights for researchers. METHODS: The articles regarding the old adults' CI in the WoS and CNKI were retrieved from 2012 to 2022. CiteSpaceV.6.1.R4 was used to generate network maps. RESULTS: Four thousand seven hundred thirteen publications and 304 publications from CNKI were retrieved. Overall, from 2012 to 2022, the trend of articles published in WoS and CNKI were increasing. Data from WoS showed that USA, University of California, Petersen RC were the most influential country, institution and author respectively; Folstein MF, Neurology and a diagnosis guideline of mild CI were the most cited author, journal and reference separately; while the keywords of CI could be summarized in 3 aspects: related disease and symptom, risk factors, manifestations. Data from CNKI illustrated that Peking Union Medical College, Dan Liu were the most influential institution and scholar respectively, while the keywords of CI could be summarized in 3 aspects: related disease and symptoms, risk factors, intervention. CONCLUSION: Articles published on old adults' CI were drawing an increasing amount of attention from 2012 to 2022 both in WoS and CNKI. Keywords of CI in WoS and CNKI both focused on risk factors, related disease and symptom, yet WoS contributed more to the mechanism and CNKI contributed more to the intervention.