{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:16:00Z","timestamp":1768436160968,"version":"3.49.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Mutations in the <jats:italic>IKBKB<\/jats:italic> gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the <jats:italic>IKBKB<\/jats:italic> gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, <jats:italic>Ikbkb<\/jats:italic> Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKK\u03b2 deficiency and impairs immune function. Here, we found that cells from both the patient and <jats:italic>Ikbkb<\/jats:italic> Y397H mice lacked or showed decreased levels of IKK\u03b2 protein, along with impaired lymphocyte function. IKK\u03b1 and IKK\u03b3 protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKK\u03b2 protein was accelerated. Binding of human NF-\u03baB to DNA in patient PBMCs fell upon stimulation with TNF-\u03b1 or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that <jats:italic>IKBKB<\/jats:italic> deficiency induces abnormal IKK\u03b2 protein degradation, leading to impaired NF-\u03baB signaling and immune function. We postulate that the Y395H variant in the IKK\u03b2 protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.<\/jats:p>","DOI":"10.3389\/fimmu.2020.517544","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T05:11:06Z","timestamp":1613365866000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["A Novel Homozygous Mutation Destabilizes IKK\u03b2 and Leads to Human Combined 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