bims-actimu 2024-11-24 papers

Issue of 2024–11–24
two papers selected by
Elodie Busch, University of Strasbourg

J Autoimmun. 2024 Nov 15. pii: S0896-8411(24)00170-7. [Epub ahead of print]149 103336

Wiskott-Aldrich syndrome protein maintains regulatory T cell tolerance by modulating their surface IL-2 receptor levels.

Qin Zhao, Wenhui Li, Wenyan Li, Yang Lu, Ting Zeng, Wenjing Zhang, Min Zhang, Lina Zhou, Yunfei An, Wenxia Song, Zhou Shu, Xiaodong Zhao.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency condition caused by ablation of functional WAS protein (WASP) expression, and associated with susceptibility to infections, eczema, and autoimmunity. Regulatory T cell (Treg) defects are an important cause of autoimmunity in WAS. Currently, the mechanisms underlying cytoskeleton involvement in Treg-regulated autoimmunity remain unclear, and WAS is an excellent model for investigation of this question. Here, we examined patients with WAS and WASP knockout (WASp-/-) mice to uncover a new mechanism involving the actin nucleation promoting factor, WASP, in regulating Treg tolerance by modulating their surface IL-2 receptor (IL-2R) levels. Surface expression levels of IL-2R and its downstream signaling molecules, phosphoinositide 3-kinase/pSTAT5, are decreased in WASp-/- Tregs. Low dosage IL-2 combined with anti-IL-2 monoclonal antibody (IL2 complex) treatment can compensate for Treg deficiency in WAS in vitro and in vivo. Moreover, IL2 complex treatment relieved autoimmune colitis in WASp-/- mice. Reduced surface IL-2R is primarily caused by elevated IL-2R internalization and degradation, and lysosomal and endosomal genes associated with these processes are upregulated in WASp-/- Tregs. Finally, spatiotemporal analysis of dynamin and Neural Wiskott Aldrich Syndrome Protein (N-WASP) recruitment, by generating lipid bilayers and total internal reflection fluorescence microscopy, showed that WASP deficiency promoted IL-2R internalization and degradation by enhancing N-WASP activation. Consistently, N-WASP inhibition in Tregs using wiskostatin reduced IL-2R internalization. Together, our results reveal a novel intrinsic role of WASP in regulation of surface IL-2R dynamics in Tregs, highlighting a potential new therapeutic approach for autoimmune diseases.

Keywords: Degradation; IL2 receptor; Internalization; Regulatory T cell; Wiskott-Aldrich syndrome protein

DOI: https://doi.org/10.1016/j.jaut.2024.103336

Nat Commun. 2024 Nov 16. 15(1): 9940

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.

Alberto Iannuzzo, Selket Delafontaine, Rana El Masri, Rachida Tacine, Giusi Prencipe, Masahiko Nishitani-Isa, Rogier T A van Wijck, Farzana Bhuyan, Adriana A de Jesus Rasheed, Simona Coppola, Paul L A van Daele, Antonella Insalaco, Raphaela Goldbach-Mansky, Takahiro Yasumi, Marco Tartaglia, Isabelle Meyts, Jérôme Delon.

Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports. Consequently, it favours STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192 C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway and the type I interferon response, and elicit endoplasmic reticulum stress. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. In conclusion, we report further mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.

DOI: https://doi.org/10.1038/s41467-024-54294-y