The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis.
CRISPR
Caspase
PANoptosis
PP6 complex
PPP6C
PPP6R1
PPP6R2
PPP6R3
RIPK1
TAK1
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
29 May 2024
29 May 2024
Historique:
received:
15
11
2023
accepted:
23
04
2024
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
28
5
2024
Statut:
epublish
Résumé
The innate immune system serves as the first line of host defense. Transforming growth factor-β-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease. In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation. Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.
Sections du résumé
BACKGROUND
BACKGROUND
The innate immune system serves as the first line of host defense. Transforming growth factor-β-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease.
RESULTS
RESULTS
In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation.
CONCLUSIONS
CONCLUSIONS
Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.
Identifiants
pubmed: 38807188
doi: 10.1186/s12915-024-01901-5
pii: 10.1186/s12915-024-01901-5
doi:
Substances chimiques
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Phosphoprotein Phosphatases
EC 3.1.3.16
RIPK1 protein, human
EC 2.7.11.1
protein phosphatase 6
EC 3.1.3.16
MAP kinase kinase kinase 7
EC 2.7.11.25
MAP Kinase Kinase Kinases
EC 2.7.11.25
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
122Subventions
Organisme : NIH HHS
ID : AI101935
Pays : United States
Organisme : NIH HHS
ID : AI124346
Pays : United States
Organisme : NIH HHS
ID : AI160179
Pays : United States
Organisme : NIH HHS
ID : AR056296
Pays : United States
Organisme : NIH HHS
ID : CA253095
Pays : United States
Informations de copyright
© 2024. The Author(s).
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