Heteromeric interference, a novel pathogenesis for human immunodeficiency.

Dear All,

Cell Signal Unit (Yamamoto Unit) would like to inform you of a seminar by Dr. Ichiro Taniuchi from RIKEN.

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Date: Thursday, April 18, 2019

Time: 13:30-14:30

Venue: D015, Level D, Lab 1

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Speaker:

Dr. Ichiro Taniuchi, RIKEN

Title:

Heteromeric interference, a novel pathogenesis for human immunodeficiency.

Abstract:
Immune system is a higher-order complexed biological system that is essential to protect our body from pathogenic organisms. Before the birth when individual begins to be exposed to pathogen-rich outer environment, essential components of immune system must be generated by developmental program embedded on genome. In other words, perturbation of this process appears as primary immune deficiencies (PID) resulting in suffering from recurrent infection. Given central roles of transcription factors (TFs) to govern immune cell development, many genetic variations that impairs TFs function have been identified as causal for PID. In some PID cases, heterozygous variation also causes PID through mechanisms such as gain-of-function, negative dominance, or haploinsufficiency. Here we show a family case for B-cell deficiency and isolated a heterozygous missense mutation in IKZF3 gene that results in a glycine to arginine replacement within the DNA binding domain of its encoded AIOLOS protein. Using a mouse model that harbors the corresponding mutation, we unravel that the mutant AIOLOS not only did not bind the canonical AIOLOS DNA sequence, but also altered the DNA binding specificity of heterodimers with IKAROS. Thus, the B-cell deficiency is caused by the missense AIOLOS mutation hijacking IKAROS function. Recently, the de novo heterozygous missense variant in the BCL11B gene, which generates a BCL11B^N441K mutant protein, was reported to be causal for T-cell deficiency. In this case, early thymocyte development is more severely inhibited in Bcl1b^D/B441K mice than in Bcll1b-deficient mice, suggesting that BCL11B^N441K mutant acts as dominant-negative against other proteins than Bcl11b. We unraveled that Bcl11b make heterodimer with Bcl11a, the most related family member, in T-cell progenitors, suggesting that the Bcl11b^N440K mutant protein interferes with Bcl11a function. Our analyses of two PID cases prompt us to propose that heteromeric interference is a novel mechanism of autosomal dominance that causes disease by impairing protein function via mutation of its heterodimeric partner.

Host:
Prof. Tadashi Yamamoto

We hope to see many of you at the seminar.

Best regards,

Yuki Nakagawa

Research Unit Administrator

Cell Signal Unit