Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer.However,key host factors that may control the generation of the inner mucus layer are rarely reported.Here,we identify a novel function of TRIM34 in goblet cells(GCs)in controlling inner mucus layer generation.Upon DSS treatment,TRIM34 deficiency led to a reduction in Muc2 secretion by GCs and subsequent defects in the inner mucus layer.This outcome rendered TRIM34-deficient mice more susceptible to DSS-induced colitis and colitis-associated colorectal cancer.Mechanistic experiments demonstrated that TRIM34 controlled TLR signaling-induced Nox/Duox-dependent ROS synthesis,thereby promoting the compound exocytosis of Muc2 by colonic GCs that were exposed to bacterial TLR ligands.Clinical analysis revealed that TRIM34 levels in patient samples were correlated with the outcome of ulcerative colitis(UC)and the prognosis of rectal adenocarcinoma.This study indicates that TRIM34 expression in GCs plays an essential role in generating the inner mucus layer and preventing excessive colon inflammation and tumorigenesis.
Infl ammasome is a large protein complex activated upon cellular stress or microbial infection,which triggers maturation of pro-inflammatory cytokines interleukin-1βand interleukin-18 through caspase-1 activation.Nod-like receptor family protein 3(NLRP3)is the most character-ized infl ammasome activated by various stimuli.However,the mechanism of its activation is unclear and its exact cellular localization is still unknown.We examined the potential co-localization of NLRP3 infl ammasome with mi-tochondria and seven other organelles under adenosine triphosphate,nigericin or monosodium urate stimulation in mouse peritoneal macrophages using confocal micros-copy approach.Our results revealed that the activated endogenous apoptosis-associated speck-like protein containing a CARD(ASC)pyroptosome forms in the cyto-plasm and co-localizes with NLRP3 and caspase-1,but not with any of the organelles screened.This study indicates that the ASC pyroptosome universally localizes within the cytoplasm rather than with any specifi c organelles.
Yan WangChen YangKairui MaoShuzhen ChenGuangxun MengBing Sun
