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Cited by 10NF-κB Signaling PathwaysImmune Response and InflammationNatural Compounds in Disease Treatment

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Serine 165 phosphorylation of SHARPIN regulates the activation of NF-κB

Open access
Thys, An, Trillet, Kilian, Rosińska, Sara, Gayraud, Audrey, Douanne, Tiphaine, Danger, Yannic, Renaud, Clotilde C.N., Antigny, Luc, Lavigne, Régis, Pineau, Charles, Com, Emmanuelle, Vérité, Franck, Gavard, Julie, Bidère, Nicolas·2021·iScience
DOI 10.1016/j.isci.2020.101939PMC PMC7773595

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Abstract

The adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex (LUBAC). This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate and has been linked to the regulation of the NF-κB pathway downstream of most immunoreceptors, inflammation, and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine at position 165 in lymphoblastoid cells and can be further induced following T cell receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark controls the linear ubiquitination of the NF-κB regulator NEMO and allows the optimal activation of NF-κB in response to TNFα. These results identify an additional layer of regulation of the LUBAC and unveil potential strategies to modulate its action.

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Crossref · 10.1016/j.isci.2020.101939

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  • S165 phosphorylation of SHARPIN is the activating phosphorylation for LUBAC activation.

    “besides the recent identification of S165 phosphorylation of SHARPIN as the activating phosphorylation for LUBAC activation (Thys, Trillet et al., 2021)”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as Thys, Trillet et al., 2021

    The Results and discussion section (page not provided) identifies S165 as SHARPIN’s main phosphorylation site and reports that its phosphorylation is required for optimal LUBAC-mediated ubiquitination of NEMO and subsequent NF-κB activation. Calling it the activating phosphorylation for LUBAC activation overstates that selective finding: the paper says its precise effect on LUBAC activity is unclear and reports no apparent effect on LUBAC stability, recruitment to TNFR1, or ubiquitination of RIPK1. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Metadata

Authors
Thys, A., Trillet, K., Rosińska, S., Gayraud, A., Douanne, T., Danger, Y., Renaud, C. C. N., Antigny, L., Lavigne, R., Pineau, C., Com, E., Vérité, F., Gavard, J., & Bidère, N.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Établissement Français du Sang (FR)
  • Inserm (FR)
Corresponding author
Bidère, Nicolas
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2021-01
Volume
24
Issue
1
Pages
101939
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2020.101939
PMC
PMC7773595
OpenAlex
W3111307700
Cited by
10
References
4
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2022: 5
FWCI
0.69
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Centre National de la Recherche Scientifique
  • Infrastructures en Biologie Santé et Agronomie
  • Fondation contre le Cancer
  • Agence Nationale de la Recherche
  • Fondation pour la Recherche Médicale (DEQ20180339184)
  • Conseil Régional de Bretagne
  • Fondation de France
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
SHARPIN, NF-κB activation, LUBAC, NEMO, linear ubiquitination, TNF signaling, T cell receptor stimulation, lymphoblastoid cell lines, E3 ubiquitin ligase, immunoreceptor signaling

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