Calpain 15 activity in immune regulation
Virology
Final Report Abstract
The innate immune system is central to fend off virus infections and operates through engagement of multiple signalling pathways, which shape the cellular defense systems. Among the most important signaling cascades are the type-I interferon system, NF-kB signalling as well as regulation of the inflammasome. Notably, many viruses developed countermeasures, which impair the activity of the innate immune system through engagement of critical factors that are central to shaping antiviral immune responses. We had found that the matrix protein long (ML) of Thogotovirus (THOV) critically contributes to viral pathogenicity. Proteomics based interactome analysis identified general transcription factor IIB (TFIIB) and the unstudied calpain protease CAPN-15 as significantly enriched binding partners. While we could establish that TFIIB blunts the interferon response, the role of CAPN15 was enigmatic. Through affinity proteomics analyses we could identify proteins of the NF-kB signalling cascade to bind to CAPN15. Indeed, we could verify that CAPN15 binds to TRAF2 and regulates NF-kB dependent gene expression. Surprisingly, however, we also identified that CAPN15 regulates the inflammasome, i.e. promotes the maturation of IL-1β and the induction of lytic cell death. ML thus impairs the induction of all relevant innate immune responses through engagement of two cellular proteins that appear to centrally regulate immune responses.
Publications
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Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature, 594(7862), 246-252.
Stukalov, Alexey; Girault, Virginie; Grass, Vincent; Karayel, Ozge; Bergant, Valter; Urban, Christian; Haas, Darya A.; Huang, Yiqi; Oubraham, Lila; Wang, Anqi; Hamad, M. Sabri; Piras, Antonio; Hansen, Fynn M.; Tanzer, Maria C.; Paron, Igor; Zinzula, Luca; Engleitner, Thomas; Reinecke, Maria; Lavacca, Teresa M. ... & Pichlmair, Andreas
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Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases. The EMBO Journal, 41(17).
Bergant, Valter; Yamada, Shintaro; Grass, Vincent; Tsukamoto, Yuta; Lavacca, Teresa; Krey, Karsten; Mühlhofer, Maria‐Teresa; Wittmann, Sabine; Ensser, Armin; Herrmann, Alexandra; vom Hemdt, Anja; Tomita, Yuriko; Matsuyama, Shutoku; Hirokawa, Takatsugu; Huang, Yiqi; Piras, Antonio; Jakwerth, Constanze A.; Oelsner, Madlen; Thieme, Susanne ... & Kato, Hiroki
