EFHD2 is broadly expressed in various cell types, with particularly high expression in neurons 12. However, whether there exists suppressive molecular machinery in the membrane trafficking of the cell death receptors such as TNFR1 in IECs remains to be fully investigated.ĮF-hand domain-containing protein D2 (also known as Swiprosin-1) is a calcium-binding protein with two conserved EF-chiral coiled-coil structural domains, and it is mostly involved in calcium signaling, cytoskeleton assembly and synapse formation 12, 13, 14. Another study revealed the mechanism of spatiotemporal regulation of IFNAR endocytosis and endosomal sorting to differential activation of JAK-STAT signaling by IFN-α and IFN-β 11. Indeed, membrane translocation and endosomal trafficking of immune receptors for cytokines, chemokines or cell death factors are verified to be important in various biological processes, but still underrated in the control of immune response and inflammation. Therefore, receptor internalization and endosomal trafficking are essential in the initiation and termination of TNFR1-mediated cell death signaling 8. A recent study has characterized ATG9A as a checkpoint of TNF-induced apoptosis by targeting LC3-independent lysosomal degradation of cytotoxic complex ΙΙa 10. Once TNFR1-complex Ι is internalized by a clathrin-mediated endocytosis, de-ubiquitylation and degradation of RIPK1 lead to the dissociation of complex Ι and the formation of complex ΙΙ, which induces apoptosis eventually 7, 8, 9. ![]() Upon TNF stimulation, TNFR1 normally recruits TRADD and RIPK1 to form complex Ι on the plasma membrane, which mediates NF-κB signaling. However, excessive intestinal epithelial cell (IEC) death in IBD conversely aggravates the defects and disorders of the epithelium barrier, leading to substantial and persistent intestinal inflammation, which eventually advances the intestinal carcinogenesis 3, 4.Īs a pleiotropic pro-inflammatory cytokine, TNF has been considered a primary driver of epithelium cell death in the intestine, and TNF blockade has achieved clinical benefit for IBD patients in clinic 5, 6. ![]() ![]() The intact epithelium and mucosal barrier jointly maintain the integrity of intestinal barrier and colonic homeostasis. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract characterized by the disrupted intestinal barrier and the severe intestinal inflammatory response 1, 2, 3. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. ![]() TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation.
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