ER stress amplifies inflammation via a dual mechanism involving IκBζ-XBP1s synergism and Regnase-1 degradation.

Authors

Yuri Nakaminami, Lerdluck Ruengsinpinya, Riko Sakihara, Yoshifumi Takahata, Kenji Hata, Takao Iwawaki, Riko Nishimura, Tomohiko Murakami

Published in

Journal of immunology (Baltimore, Md. : 1950). Volume 215. Issue 6. Jun 07, 2026.

Abstract

Inflammatory diseases arise from complex interactions between immune signaling and cellular stress. Although endoplasmic reticulum (ER) stress is a key modulator of immunity, the mechanisms by which it promotes inflammatory pathology remain incompletely understood. Notably, ER stress-induced NF-κB activation alone is insufficient to account for robust IL-6 production, thus suggesting the involvement of additional regulators. Using bone marrow-derived macrophages and sepsis model mice, we identified the inducible transcription factor IκBζ as a critical mediator of this response, with ER stress synergizing with TLR signaling to markedly upregulate IκBζ. Mechanistically, ER stress triggered calcium-dependent signaling that led to IκB kinase-mediated degradation of the RNase Regnase-1, likely stabilizing Nfkbiz mRNA and promoting the accumulation of IκBζ, which was found to cooperate with the ER stress factor XBP1s to drive transcription of selected secondary-response genes, particularly Il6 and Nos2. Importantly, this synergy was required for excessive IL-6 production in septic mice, highlighting a gene-specific amplification pathway. Together, these findings identify a dual mechanism in which transcriptional synergy between IκBζ and XBP1s is coupled to posttranscriptional mRNA stabilization via Regnase-1 degradation, thereby linking proteotoxic stress to hyperinflammatory responses. Our results establish ER stress-mediated IκBζ accumulation as a key driver of inflammatory pathogenesis and a potential therapeutic target in ER stress-associated inflammatory disorders.

PMID:
42364119
Bibliographic data and abstract were imported from PubMed on 28 Jun 2026.

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