RIPK2 blocking peptide

Objective: Host genetic factors play an important role in susceptibility to Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB). Receptor interacting-serine/threonine-protein kinase 2 (RIPK2) is a critical adapter protein for signal propagation of NOD2, dysregulation of which leads to defects in bacterial detection. To investigate the role of RIPK2 on the susceptibility of tuberculosis, we conducted a large sample size case-control study in a Western Chinese Han population. Methods: Five single-nucleotide polymorphisms (SNPs) within or near to RIPK2 were genotyped in 1359 TB cases and 1534 controls using the improved multiplex ligation detection reaction method in a case-control study. Results: Of the five variants, rs39509 was observed to be associated with TB risk in the allelic effects (P = 0.015), additive (P = 0.020) and recessive model (P = 0.005) after Bonferroni correction. Rs39509 might fall in putative functional regions and might be eQTL for the RIPK2 and long non-coding RNA RP11-37B2.1 according to the Genotype-Tissue Expression (GTEx) Project. Conclusions: Our findings firstly exhibit that the G allele of rs39509 in nearGene-3 region of RIPK2 might serve as a hazard for TB in this Western Chinese Han population. Further validation studies on a variety of ethnic populations and function experiments are needed to confirm the roles of the variants identified.

Objective Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. Design We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). Results Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. Conclusions NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.