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. Wijck, Farzana Bhuyan, Adriana A. Jesus Rasheed, Simona Coppola, Paul L. A. Daele, Antonella Insalaco, Raphaela Goldbach-Mansky, Takahiro Yasumi, Marco Tartaglia, Isabelle Meyts and Jérôme Delon ()
Additional contact information
Alberto Iannuzzo: Institut Cochin
Selket Delafontaine: KU Leuven
Rana El Masri: Institut Cochin
Rachida Tacine: Institut Cochin
Giusi Prencipe: IRCCS
Masahiko Nishitani-Isa: Kyoto University Graduate School of Medicine
Rogier T. A. Wijck: Erasmus University Medical Center
Farzana Bhuyan: National Institutes of Health
Adriana A. Jesus Rasheed: National Institutes of Health
Simona Coppola: Istituto Superiore di Sanità
Paul L. A. Daele: Erasmus University Medical Center
Antonella Insalaco: IRCCS Ospedale Pediatrico Bambino Gesù
Raphaela Goldbach-Mansky: National Institutes of Health
Takahiro Yasumi: Kyoto University Graduate School of Medicine
Marco Tartaglia: IRCCS
Isabelle Meyts: KU Leuven
Jérôme Delon: Institut Cochin

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54294-y

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