Tumor suppressor p53 regulates intestinal type 2 immunity

Abstract

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

Jaw1/LRMP increases Ca2+ influx upon GPCR stimulation with heterogeneous effect on the activity of each ITPR subtype

“…We previously reported that Jaw1 is localized on the ER and the outer nuclear membrane, and it is associated with nuclear shape maintenance 16 . Furthermore, Jaw1 was recently reported to interact with all ITPR subtypes via its coiled-coil domain, and the deletion of Jaw1 in mouse embryonic fibroblast (MEF) reduces Ca 2+ influx into the cytoplasm upon ionomycin stimulation, a reagent that increases cell membrane ion permeability 13 . However, whether and how Jaw1 is involved in the calcium dynamics under physiological conditions, such as GPCR stimulation-related aspects, remains unclear.…”

Enteric Tuft Cells in Host-Parasite Interactions

“…ETCs also produce and release cysteinyl leukotrienes (CysLTs), potent eicosanoid lipid mediators, in response to N. brasiliensis and H. polygyrus but not Tritrichomonas musculis [57]. Recently, murine ETCs were shown to activate the tumor suppressor gene p53 following N. brasileinsis and Tritrichomonas muris infection [73]. One consequence of this p53 activation was upregulated expression of the lymphoid-restricted membrane protein (LRMP1), which, in association with the channel protein ITPR2 (Inositol 1,4,5-Trisphosphate Receptor Type 2), coordinates the release of Ca 2+ ions and subsequent release of IL-25 via TRPM5 [73].…”

“…Recently, murine ETCs were shown to activate the tumor suppressor gene p53 following N. brasileinsis and Tritrichomonas muris infection [73]. One consequence of this p53 activation was upregulated expression of the lymphoid-restricted membrane protein (LRMP1), which, in association with the channel protein ITPR2 (Inositol 1,4,5-Trisphosphate Receptor Type 2), coordinates the release of Ca 2+ ions and subsequent release of IL-25 via TRPM5 [73]. This adds another level of intracellular control over IL-25 to regulate the activation of a Th2 cascade.…”

Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces

“…IP 3 then binds its cognate receptor IP 2 R in the small intestine or IP 3 R in the airway and causes calcium efflux from the endoplasmic reticulum. Calcium efflux also appears to require interactions between Inositol 1,4,5-Triphosphate Receptor Associated 2 (IRAG2) with IP 3 receptors [ 40 ]. Intracellular calcium flux activates transient receptor potential cation channel subfamily M member 5 (TRPM5), which allows sodium influx and subsequent cellular depolarization.…”

“…The transcriptional regulation driving expression of tuft cell signaling components is poorly characterized, but it is known that p53 regulates expression of the transmembrane protein coding gene Irag2 , which is required for calcium flux. Additional molecules that activate tuft cells likely exist that have not been discovered [ 23 , 29 , 31 , 40 , 43 , 47 , 49 – 55 ]. GNAT3, G Protein Subunit Alpha Transducin 3; GPCR, G protein–coupled receptor; IRAG2, Inositol 1,4,5-Triphosphate Receptor Associated 2; PLCβ2, phospholipase C beta 2.…”