Valosin-containing protein-regulated endoplasmic reticulum stress causes NOD2-dependent inflammatory responses

Journal article

NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p. E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient's cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p. E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.

Authors: Ghalandary, M; Li, Y; Fröhlich, T; Magg, T; Liu, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 12
• Issue: 1
• Pages: 3906-3906
• Article number: 3906
• Publication date: 2022-03-10
• DOI: 10.1038/s41598-022-07804-1
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Biology; Cell culture; Immunology; Chemistry; Unfolded protein response; Cell biology; Inflammation; Gene; Chemokine; Endoplasmic reticulum; Gene knockdown; Genetics; Tunicamycin; Mutant; NOD2; Immune system; Innate immune system; CXCL2; Proinflammatory cytokine; CXCL1; Muramyl dipeptide