查看更多>>摘要：Legionella pneumophilais a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires'disease.During infections,L.pneumophila releases over 300 effector proteins into host cells through an Icm/Dot type IV secretion system to manipulate the host defense system for survival within the host.Notably,certain effector proteins mediate posttranslational modifications(PTMs),serving as useful approaches exploited by L.pneumophila to modify host proteins.Some effectors catalyze the addition of host protein PTMs,while others mediate the removal of PTMs from host proteins.In this review,we summarize L.pneumophila effector-mediated PTMs of host proteins,including phosphorylation,ubiquitination,glycosylation,AMPylation,phosphocholination,methylation,and ADP-ribosylation,as well as dephosphorylation,deubiquitination,deAMPylation,deADP-ribosylation,dephosphocholination,and delipidation.We describe their molecular mech-anisms and biological functions in the regulation of bacterial growth and Legionella-containing vacuole biosynthesis and in the disruption of host immune and defense machinery.
查看更多>>摘要：Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion and β-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducible β-cell-specific Brsk2knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
查看更多>>摘要：Hyperglycaemia-induced oxidative stress may disrupt insulin secretion and β-cell survival in diabetes mellitus by overproducing reactive oxygen species.Human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)exhibit antioxidant properties.However,the mechanisms by which hUC-MSCs protect β-cells from high glucose-induced oxidative stress remain underexplored.In this study,we showed that intravenously injected hUC-MSCs engrafted into the injured pancreas and promoted pancreatic β-cell function in a mouse model of type 1 diabetes mellitus.The in vitro study revealed that hUC-MSCs attenuated high glucose-induced oxidative stress and prevented β-cell impairment via the Nrf2/HO-1 signalling pathway.Nrf2 knockdown partially blocked the anti-oxidative effect of hUC-MSCs,resulting in β-cell decompensation in a high-glucose environment.Overall,these findings provide novel insights into how hUC-MSCs protect β-cells from high glucose-induced oxidative stress.
查看更多>>摘要：To facilitate survival,replication,and dissemination,the intracellular pathogen Legionella pneumophila relies on its unique type IVB secretion system(T4SS)to deliver over 330 effectors to hijack host cell pathways in a spatiotemporal manner.The effectors and their host targets are largely unexplored due to their low sequence identity to the known proteins and functional redundancy.The T4SS effector SidN(Lpg1083)is secreted into host cells during the late infection period.However,to the best of our knowledge,the molecular characterization of SidN has not been studied.Herein,we identified SidN as a nuclear envelope-localized effector.Its structure adopts a novel fold,and the N-terminal domain is crucial for its specific subcellular localization.Furthermore,we found that SidN is transported by eukaryotic karyopherin Importin-13 into the nucleus,where it attaches to the N-terminal region of Lamin-B2 to interfere with the integrity of the nuclear envelope,causing nuclear membrane disruption and eventually cell death.Our work provides new insights into the structure and function of an L.pneumophila effector protein,and suggests a potential strategy utilized by the pathogen to promote host cell death and then escape from the host for secondary infection.
查看更多>>摘要：Alpha-fetoprotein(AFP)is the most widely used biomarker for the diagnosis of hepatocellular carcinoma(HCC).However,a substantial proportion of HCC patients have either normal or marginally increased AFP levels in serum,and the underlying mechanisms are not fully understood.In the present study,we providedin vitroandin vivoevidence that heat shock protein gp96 promoted AFP expression at the transcriptional level in HCC.NR5A2 was identified as a key transcription factor for the AFP gene,and its stability was enhanced by gp96.A further mechanistic study by co-immunoprecipitation,GST pull-down,and molecular docking showed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539.The binding of gp96 inhibited SUMOylation,ubiquitination,and subsequent degradation of NR5A2.In addition,clinical analysis of HCC patients indicated that gp96 expression in tumors was positively correlated with serum AFP levels.Therefore,our study uncovered a novel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.
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