The E3 ligase RNF32 controls the IκB kinase complex and NF-κB signaling in intestinal stem cells

Nuclear factor κB (NF-κB) signaling is a central pathway regulating a plethora of cellular functions. Here, we find that RNF32, a RING E3 ubiquitin ligase whose expression is enriched in murine intestinal stem cells, regulates the activity of the IκB kinase (IKK) complex, the signal integration hub for NF-κB activation. The E3 ligase activity of RNF32 depends on calmodulin, the primary calcium sensor in eukaryotic cells. Increased levels of intracellular calcium ion (Ca<sup>2+</sup>) induce RNF32 binding to calmodulin, RNF32 activation, and autoubiquitylation. In turn, polyubiquitin chains conjugated to RNF32 recruit NEMO, the regulatory subunit of the IKK complex. Moreover, Ca<sup>2+</sup> rise triggers RNF32 phase separation, which is required for the formation of NEMO condensates and IKK activation. Finally, we show that RNF32 is required for NF-κB activation triggered by bacterial lipopolysaccharides. Collectively, our findings uncover a mechanism controlling NF-κB signaling in the intestinal epithelium.

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Publication Details

Journal
Molecular Cell
Published
2025-10-29
DOI
https://doi.org/10.1016/j.molcel.2025.10.005
Citations
1
Primary Topic
NF-κB Signaling Pathways
Type
article
Field-Weighted Citation Impact
0.94
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article

The E3 ligase RNF32 controls the IκB kinase complex and NF-κB signaling in intestinal stem cells

Angela Lauriola, Simona Polo, Elena Maspero, Mariapina D’Onofrio et al.
1 citations
Molecular Cell
NF-κB Signaling Pathways
0.94
article

The E3 ligase RNF32 controls the IκB kinase complex and NF-κB signaling in intestinal stem cells

Angela Lauriola, Simona Polo, Elena Maspero, Mariapina D’Onofrio, Nicola Vitulo, Andrea Vettori, Juliana Haydeé Enriqué Steinberg, Michael Assfalg, Akihiro Yasue, Marco Pedretti, Vincenzo Taibi, F Rossi, Alessandra Astegno, Yasusei Kudo, Spartaco Santi, Yasuhiro Mouri, Mario Rossi, Daniele Guardavaccaro, Motoharu Sarubo, Mohsen Hajisadeghian
article en
1 citations

Abstract

Nuclear factor κB (NF-κB) signaling is a central pathway regulating a plethora of cellular functions. Here, we find that RNF32, a RING E3 ubiquitin ligase whose expression is enriched in murine intestinal stem cells, regulates the activity of the IκB kinase (IKK) complex, the signal integration hub for NF-κB activation. The E3 ligase activity of RNF32 depends on calmodulin, the primary calcium sensor in eukaryotic cells. Increased levels of intracellular calcium ion (Ca<sup>2+</sup>) induce RNF32 binding to calmodulin, RNF32 activation, and autoubiquitylation. In turn, polyubiquitin chains conjugated to RNF32 recruit NEMO, the regulatory subunit of the IKK complex. Moreover, Ca<sup>2+</sup> rise triggers RNF32 phase separation, which is required for the formation of NEMO condensates and IKK activation. Finally, we show that RNF32 is required for NF-κB activation triggered by bacterial lipopolysaccharides. Collectively, our findings uncover a mechanism controlling NF-κB signaling in the intestinal epithelium.

Molecular CellVol. 85(22)
University of Verona (IT), Austral University (AR), IFOM (IT), Istituto di Genetica Molecolare (IT), Nitobe Memorial Nakano General Hospital (JP), Tokushima University (JP)
Openalex Percentile: Top 19%
NF-κB Signaling Pathways
0.94
DOIOpen Access PDFOpenAlex
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