adcb91DCThe immune system consists of many types of hematopoietic cells. The de-12.90.664.892.732Heterodimeric interferenceIKAROSAIOLOSMouse modelAiolos+/+AiolosG158R/G158RDNA bindingG159RChIP-seqAiolosWTIkarosAiolosG158RIkaros“Impediment”of physiological bindingsites“Sequestration”to abnormal binding sitesDimerizationHuman patientIKAROSAIOLOSHealthy controlCD3heterodimerB cell deficiencyAIOLOSG159RIKAROSActivity ↓AutosomalDominantPatientvelopment of those immune cells from hematopoietic stem cells is regulat-ed by the precise decoding of genomic information by transcription factors. My laboratory has been addressing how transcription factors control immune cell development. Lymphocytes with a variety of antigen-specificities are the main players in the adaptive immune system. The primary developmental program of T lymphocytes that occurs in the thymus has been evolved to select useful and non-self-reactive immune soldiers using a sophisticated nuclear program that integrates environmental cues sensed by T cell antigen receptors (TCR). Another research aim in my laboratory is to understand how TCR signals are sensed and are coupled with cell fate determination programs in the nucleus by using the helper-versus cytotoxic-lineage choice as a model.Inborn errors in immunity (IEI), also known as primary immunodeficien-cies (PID), are genetic disorders that result in increased susceptibility to in-fectious disease, autoinflammatory disease and autoimmunity. IEIs are often caused by genetic variants in a single gene. Animal models serve as a powerful resource to unravel the pathogenesis of IEIs. By characterizing two familial IEI cases, we identified two AIOLOS variants, AIOLOSG159R and AIOLOSN160S, as causal for the IEIs. IKAROS family proteins, which consist of six members, function as homo- or heterodimers. Using mouse models harboring the cor-responding human variant AIOLOSG159R, we revealed that AIOLOSG159R protein hijacks IKAROS function at least by sequestration of IKAROS protein from its normal binding genomic regions. We designate this novel pathogenic mecha-nism caused by autosomal dominance as “heterodimeric interference”, a con-cept that could be applied to a wide range of diseases caused by a disorder of multimer protein complexes.Figure: A heterodimeric interference is a novel pathogenic mechanism for inborn errors of im-munity (IEI)(a) Structure of IKAROS and AIOLOS proteins. IKZF family proteins possess four Zinc -finger and two Zinc-finger domains at the middle and C-terminus, respectively. We isolated an AIOLOSG159R missense variant from a human IEI family case. (b) Flow cytometry analyses of periph-eral blood showing a lack of CD19+ B lymphocytes in the patient. (c) ChIP-seq analyses using thymocytes from a mouse harboring the corresponding mutation AiolosG158R revealed impaired DNA binding of wild type Ikaros when Ikaros formed a heterodimer with mutant AiolosG158R protein. (d) Graphic summary of the novel pathogenic mechanism, heterodimeric interference, for autosomal dominant genetic disorders. IKAROS function is hijacked by the AIOLOSG159R variant.Recent Major PublicationsYamashita M, Kuehn HS, Okuyama K, Okada S, Inoue Y, Mitsuiki N, Imai K, Takagi M, Kanegane H, Takeuchi M, Shimojo N, Tsumura M, Padhi AK, Zhang KYJ, Boisson B, Casanova JL, Ohara O, Rosenzweig SD, Taniuchi I, Morio T. A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. Nat Immunol 22, 893-903 (2021)Kuehn HS, Chang J, Yamashita M, Niemela JE, Zou C, Okuyama K, Harada J, Stoddard JL, Nunes-Santos CJ, Boast B, Baxter RM, Hsieh EWY, Garofalo M, Fleisher TA, Morio T, Taniuchi I, Dutmer CM, Rosenzweig SD. T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIO-LOS defect in patients. J Exp Med 218, e20211118 (2021)Andrews LP, Vignali KM, Szymczak-Workman AL, Burton AR, Brunazzi EA, Ngiow SF, Harusato A, Sharpe AH, Wherry EJ, Taniuchi I, Workman CJ, Vignali DAA. A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells. Immunity 54, 2209-2217 (2021)Invited presentationsTaniuchi I. “Novel pathogenesis of human primary im-munodeficiency by missense variants in transcription factors” 14th International Symposium on Nanomedi-cine (Matsue, Japan/Online) November 2021Okuyama K. “Transcriptional regulation and chromatin remodeling by a zinc finger protein, Bcl11b” 17th Pri-mate Research Forum (Tsukuba, Japan) November 2021Taniuchi I. “Aging-related changes in thymic microen-vironment in mice” RIKEN IMS Joint Human and Mouse Cell Atlas Meeting (Yokohama, Japan/Online) October 2021Laboratory for Transcriptional RegulationTeam Leader: Ichiro Taniuchi
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