New Perspectives on Paracrine IL-18 Signaling in the Intestinal Epithelium.

IL-18 is a member of the IL-1 family of cytokines, which is highly expressed in intestinal epithelial cells (IECs). Upon barrier breach, IL-18 is matured to its bioactive form as a result of inflammasome activation, released from the cell via Gasdermin D pores, and sensed by IL-18 receptor 1-positive (IL18R1) immune cells to initiate an inflammatory response. In addition to this epithelial-out signaling network, we recently uncovered an epithelial-intrinsic IL-18 signaling pathway in the murine small intestine and identified enterochromaffin cells and revival stem cells (revSC) as IL18R1 bearing IEC populations in the recovering crypt.

Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury.

ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury.

The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury.

Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1 lamina propria cells. Notably, is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized.

Cross-kingdom-mediated detection of intestinal protozoa through NLRP6.

Intestinal protists are detected by the host innate immune system through mechanisms that remain poorly understood. Here, we demonstrate that Tritrichomonas protozoa induce thickening of the colonic mucus in an NLRP6-, ASC-, and caspase-11-dependent manner, consistent with the activation of sentinel goblet cells. Mucus growth is recapitulated with cecal extracts from Tritrichomonas-infected mice but not purified protozoa, suggesting that NLRP6 may detect infection-induced microbial dysbiosis.

Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation.

Single-point mutations are pivotal in molecular zoology, shaping functions and influencing genetic diversity and evolution. Here we study three such genetic variants of a mechano-responsive protein, cadherin-23, that uphold the structural integrity of the protein, but showcase distinct genotypes and phenotypes. The variants exhibit subtle differences in transient intra-domain interactions, which in turn affect the anti-correlated motions among the constituent β-strands.

Restoring protein glycosylation with GlycoShape.

Despite ground-breaking innovations in experimental structural biology and protein structure prediction techniques, capturing the structure of the glycans that functionalize proteins remains a challenge. Here we introduce GlycoShape ( https://glycoshape.org ), an open-access glycan structure database and toolbox designed to restore glycoproteins to their native and functional form in seconds.