Frontiers in Immunology (Feb 2021)
A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency
- Tao Qin,
- Tao Qin,
- Tao Qin,
- Tao Qin,
- Tao Qin,
- Yanjun Jia,
- Yanjun Jia,
- Yanjun Jia,
- Yanjun Jia,
- Yanjun Jia,
- Yuhang Liu,
- Yuhang Liu,
- Yuhang Liu,
- Yuhang Liu,
- Yuhang Liu,
- Rongxin Dai,
- Rongxin Dai,
- Rongxin Dai,
- Rongxin Dai,
- Rongxin Dai,
- Lina Zhou,
- Lina Zhou,
- Lina Zhou,
- Lina Zhou,
- Lina Zhou,
- Satoshi Okada,
- Miyuki Tsumura,
- Hidenori Ohnishi,
- Zenichiro Kato,
- Zenichiro Kato,
- Hirokazu Kanegane,
- Xiulian Sun,
- Xiaodong Zhao,
- Xiaodong Zhao,
- Xiaodong Zhao,
- Xiaodong Zhao,
- Xiaodong Zhao
Affiliations
- Tao Qin
- Department of Infection, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Tao Qin
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Tao Qin
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Tao Qin
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Tao Qin
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Yanjun Jia
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Yanjun Jia
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Yanjun Jia
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Yanjun Jia
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Yanjun Jia
- Department of Rheumatism and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Yuhang Liu
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Yuhang Liu
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Yuhang Liu
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Yuhang Liu
- Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Yuhang Liu
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Rongxin Dai
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Rongxin Dai
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Rongxin Dai
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Rongxin Dai
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Rongxin Dai
- Department of Rheumatism and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Lina Zhou
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Lina Zhou
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Lina Zhou
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Lina Zhou
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Lina Zhou
- Department of Rheumatism and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
- Miyuki Tsumura
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
- Hidenori Ohnishi
- 0Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
- Zenichiro Kato
- 0Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
- Zenichiro Kato
- 1Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
- Hirokazu Kanegane
- 2Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Xiulian Sun
- 3Department of Brain Research Institute, Qilu Hospital of Shandong University, Shandong, China
- Xiaodong Zhao
- National Clinical Research Center for Child Health and Disorders, Chongqing, China
- Xiaodong Zhao
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Xiaodong Zhao
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
- Xiaodong Zhao
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Xiaodong Zhao
- Department of Rheumatism and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China
- DOI
- https://doi.org/10.3389/fimmu.2020.517544
- Journal volume & issue
-
Vol. 11
Abstract
Mutations in the IKBKB gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the IKBKB gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Ikbkb Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Ikbkb Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that IKBKB deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.
Keywords
