TAK1 regulates Paneth cell integrity partly through blocking necroptosis

Abstract

Paneth cells reside at the base of crypts of the small intestine and secrete antimicrobial factors to control gut microbiota. Paneth cell loss is observed in the chronically inflamed intestine, which is often associated with increased reactive oxygen species (ROS). However, the relationship between Paneth cell loss and ROS is not yet clear. Intestinal epithelial-specific deletion of a protein kinase Tak1 depletes Paneth cells and highly upregulates ROS in the mouse model. We found that depletion of gut bacteria or myeloid differentiation factor 88 (Myd88), a mediator of bacteria-derived cell signaling, reduced ROS but did not block Paneth cell loss, suggesting that gut bacteria are the cause of ROS accumulation but bacteria-induced ROS are not the cause of Paneth cell loss. In contrast, deletion of the necroptotic cell death signaling intermediate, receptor-interacting protein kinase 3 (Ripk3), partially blocked Paneth cell loss. Thus, Tak1 deletion causes Paneth cell loss in part through necroptotic cell death. These results suggest that TAK1 participates in intestinal integrity through separately modulating bacteria-derived ROS and RIPK3-dependent Paneth cell loss.

TAK1 regulates endothelial cell necroptosis and tumor metastasis

“…However, even though the prosurvival function of TAK1 in different cell types is well established, it is not fully understood how loss of TAK1 results in the rerouting of signaling pathways from prosurvival toward cell death. Different factors including the initial stimuli, the cell type and its cellular context seem to be involved [11,[35][36][37][38][39]. In most cases, TAK1 activation engages NF-κB signaling pathways to transcriptionally regulate genes involved in preventing cell death [40,41].…”

Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation inTAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome

“…TAK1 is a TGF‐beta activated kinase that has been identified as a key regulator in inflammatory and immune signaling pathways. As such, this protein has been targeted for potential therapeutic treatment of a number of inflammatory disorders, such as Crohn's disease . Finally, TAB1 interacts with and activates TAK1 independently of TAB2.…”

“…As such, this protein has been targeted for potential therapeutic treatment of a number of inflammatory disorders, such as Crohn's disease. 22 Finally, TAB1 interacts with and activates TAK1 independently of TAB2. TAB1 has a unique alpha-helix binding domain that corresponds with a binding pocket on TAK1, providing a hydrophobic association between the protein activator, TAB1, and its target, TAK1.…”

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

“…TAK1 in intestinal epithelial cells exhibited cytoprotective roles in chemical (DSS)-induced colitis (Kim et al 2009). The protective role of TAK1 is believed to be due to the maintenance of Paneth cell integrity via restraining necroptosis (Simmons et al 2016). In contrast, phosphorylation/activation of TAK1 was increased in ileum from patients with CD and correlated with tissue fibrosis (Grillo et al 2015).…”