Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42R186C, we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42R186C protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42*192C*24 that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation.
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6 June 2022
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April 28 2022
Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation
Masahiko Nishitani-Isa
,
(Conceptualization, Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Kojiro Mukai
,
2
Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
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Yoshitaka Honda
,
Yoshitaka Honda
(Investigation, Writing - review & editing)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
3
Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
4
Department of Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Hiroshi Nihira
,
Hiroshi Nihira
(Conceptualization)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Takayuki Tanaka
,
Takayuki Tanaka
(Conceptualization, Methodology, Supervision, Writing - review & editing)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Hirofumi Shibata
,
Hirofumi Shibata
(Conceptualization, Investigation, Methodology)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Kumi Kodama
,
Kumi Kodama
(Investigation, Validation)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Eitaro Hiejima
,
Eitaro Hiejima
(Supervision, Validation)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Kazushi Izawa
,
Kazushi Izawa
(Conceptualization, Funding acquisition, Investigation, Supervision)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Yuri Kawasaki
,
Yuri Kawasaki
(Resources)
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Mitsujiro Osawa
,
Mitsujiro Osawa
(Resources, Validation)
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Yu Katata
,
Yu Katata
(Resources)
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
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Sachiko Onodera
,
Sachiko Onodera
(Resources, Validation)
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
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Tatsuya Watanabe
,
Tatsuya Watanabe
(Data curation)
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
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Takashi Uchida
,
Takashi Uchida
(Data curation)
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
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Shigeo Kure
,
Shigeo Kure
(Conceptualization, Project administration, Supervision)
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
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Junko Takita
,
Junko Takita
(Writing - review & editing)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Osamu Ohara
,
Osamu Ohara
(Methodology)
8
Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
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Megumu K. Saito
,
Megumu K. Saito
(Investigation, Resources)
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Ryuta Nishikomori
,
Ryuta Nishikomori
(Conceptualization, Funding acquisition, Resources, Validation)
9
Department of Pediatrics, Kurume University Graduate School of Medicine, Kurume, Japan
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Tomohiko Taguchi
,
Tomohiko Taguchi
(Funding acquisition, Project administration, Visualization)
2
Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
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Yoji Sasahara
,
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
Yoji Sasahara: ysasahara@med.tohoku.ac.jp
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Takahiro Yasumi
(Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Correspondence to Takahiro Yasumi: yasumi@kuhp.kyoto-u.ac.jp
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Masahiko Nishitani-Isa
Conceptualization, Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
2
Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
Yoshitaka Honda
Investigation, Writing - review & editing
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
3
Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
4
Department of Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Hiroshi Nihira
Conceptualization
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Takayuki Tanaka
Conceptualization, Methodology, Supervision, Writing - review & editing
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Hirofumi Shibata
Conceptualization, Investigation, Methodology
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Kumi Kodama
Investigation, Validation
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Eitaro Hiejima
Supervision, Validation
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Kazushi Izawa
Conceptualization, Funding acquisition, Investigation, Supervision
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Yuri Kawasaki
Resources
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Mitsujiro Osawa
Resources, Validation
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Yu Katata
Resources
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
Sachiko Onodera
Resources, Validation
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
Tatsuya Watanabe
Data curation
6
Department of Neonatology, Miyagi Children’s Hospital, Sendai, Japan
Takashi Uchida
Data curation
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
Shigeo Kure
Conceptualization, Project administration, Supervision
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
Junko Takita
Writing - review & editing
1
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Osamu Ohara
Methodology
8
Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
Megumu K. Saito
Investigation, Resources
5
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Ryuta Nishikomori
Conceptualization, Funding acquisition, Resources, Validation
9
Department of Pediatrics, Kurume University Graduate School of Medicine, Kurume, Japan
Tomohiko Taguchi
Funding acquisition, Project administration, Visualization
2
Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
7
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
Correspondence to Takahiro Yasumi: yasumi@kuhp.kyoto-u.ac.jp
Yoji Sasahara: ysasahara@med.tohoku.ac.jp
*
M. Nishitani-Isa and K. Mukai contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
September 06 2021
Revision Received:
February 28 2022
Accepted:
March 31 2022
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding
Funder(s):
Japan Society for the Promotion of Science
- Award Id(s): 21K07795,20H03202,19H00974
Funder(s):
Japan Agency for Medical Research and Development
- Award Id(s): JP20ek0109387,JP21bm0104001,JP21bm0804005,JP19bm0804001,JP20gm5910025
Funder(s):
Ministry of Health, Labour and Welfare
Funder(s):
Mochida Memorial Foundation for Medical and Pharmaceutical Research
© 2022 Nishitani-Isa et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2022) 219 (6): e20211889.
Article history
Received:
September 06 2021
Revision Received:
February 28 2022
Accepted:
March 31 2022
Citation
Masahiko Nishitani-Isa, Kojiro Mukai, Yoshitaka Honda, Hiroshi Nihira, Takayuki Tanaka, Hirofumi Shibata, Kumi Kodama, Eitaro Hiejima, Kazushi Izawa, Yuri Kawasaki, Mitsujiro Osawa, Yu Katata, Sachiko Onodera, Tatsuya Watanabe, Takashi Uchida, Shigeo Kure, Junko Takita, Osamu Ohara, Megumu K. Saito, Ryuta Nishikomori, Tomohiko Taguchi, Yoji Sasahara, Takahiro Yasumi; Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation. J Exp Med 6 June 2022; 219 (6): e20211889. doi: https://doi.org/10.1084/jem.20211889
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