bims-actimu Biomed News
on Actinopathies in inborn errors of immunity
Issue of 2025–08–03
two papers selected by
Elodie Busch, University of Strasbourg
  1. β-Actin Deficiency in Baraitser-Winter Syndrome Type 1 Disrupts T-Cell Function and Immune Regulation: Implications for Targeted Therapy in Actinopathies.
  2. Cdc42 defect reveals insights into microvilli organization and function in T cell immunity.
  1. J Clin Immunol. 2025 Aug 01. 45(1): 120
    β-Actin Deficiency in Baraitser-Winter Syndrome Type 1 Disrupts T-Cell Function and Immune Regulation: Implications for Targeted Therapy in Actinopathies.
    Zahala Bar-On, Or Reuven, Atar Lev, Amos J Simon, Wajeeh Salaymeh, Alit Shalom, Raz Somech, Ortal Barel, Sigal Porges, Elisheva Javasky, Vered Molho-Pessach, Zvi Granot, Dan Bijaoui, Tzahi Neuman, Yuval Tal, Michal Baniyash, Michael Berger, Oded Shamriz.
       PURPOSE: Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in ACTB, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of ACTB mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel ACTB variant in a patient with BRWS1.
    METHODS: Whole-exome sequencing identified a heterozygous ACTB p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant ACTB constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated.
    RESULTS: The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation.
    CONCLUSION: BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.
    Keywords:  ACTB; Actinopathies; Baraitser-Winter syndrome type 1; Immune regulation; T cells; β-Actin
    DOI:  https://doi.org/10.1007/s10875-025-01906-x
  2. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505291122
    Cdc42 defect reveals insights into microvilli organization and function in T cell immunity.
    Won-Chang Soh, Sang-Moo Park, Jeong-Su Park, Hatice Karabulut, Hee-Tae Kang, Sun-Kyoung Kang, Min-Sang Kim, Jihwan Park, Sunjae Lee, Hye-Ran Kim, Chang-Duk Jun.
      Microvilli on T cells differ from those on epithelial cells, exhibiting filopodia-like characteristics that facilitate the clustering of molecules essential for sensing and cell migration. Recently, they have also been recognized as the structures from which T cell immunological synaptosomes (TIS) are released. In this study, we examined a key determinant of microvilli organization during T cell development and explored the functional roles of these structures, particularly in relation to T cell behaviors. During thymocyte maturation, single-positive thymocytes were found to develop more and longer microvilli than double-positive thymocytes. However, the deletion or inhibition of Cdc42, a small Rho family protein, significantly reduced both the number and length of microvilli in single-positive thymocytes, leading to decreased cell mass. This reduction in microvilli correlates with a decrease in antigen recognition, leading to diminished T cell activation and adhesion, as well as reduced TIS production, while intrinsic migratory properties remain unaffected. These findings highlight the filopodia-like characteristics of T cell microvilli. In this context, Cdc42 contributes significantly to microvilli formation, thereby shaping T cell function.
    Keywords:  Cdc42; T cell activation; T cell microvilli
    DOI:  https://doi.org/10.1073/pnas.2505291122
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒29 at 12:52.