Dataset Information

Casein kinase-1?1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3.

ABSTRACT: Upon necroptosis activation, receptor interacting serine/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein kinase 1 gamma (CK1?) as a candidate necroptosis-promoting factor. Here, we show that the decreased activity or amounts of CK1?1 and CK1?3, either by treatment with a chemical inhibitor or knockdown in cells, reduced TNF?-induced necroptosis. Conversely, ectopic expression of CK1?1 or CK1?3 exacerbated necroptosis, but not apoptosis. Similar to RIPK1 and RIPK3, CK1?1 was also cleaved at Asp343 by caspase-8 during apoptosis. CK1?1 and CK1?3 formed a protein complex and were recruited to the necrosome harboring RIPK1, RIPK3 and MLKL. In particular, an autophosphorylated form of CK1?3 at Ser344/345 was detected in the necrosome and was required to mediate the necroptosis. In addition, in vitro assays with purified proteins showed that CK1? phosphorylated RIPK3, affecting its activity, and in vivo assays showed that the CK1?-specific inhibitor Gi prevented abrupt death in mice with hypothermia in a model of TNF?-induced systemic inflammatory response syndrome. Collectively, these data suggest that CK1?1 and CK1?3 are required for TNF?-induced necroptosis likely by regulating RIPK3.

SUBMITTER: Lee SY

PROVIDER: S-EPMC6892881 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3.

Lee Song-Yi SY Kim Hyunjoo H Li Cathena Meiling CM Kang Jaemin J Najafov Ayaz A Jung Muhah M Kang Soosung S Wang Shaomeng S Yuan Junying J Jung Yong-Keun YK

Cell death & disease 20191204 12

Upon necroptosis activation, receptor interacting serine/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein ...[more]

PMID: 31801942

Similar Datasets

Project description:BACKGROUND:Programmed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive. METHODS:We examined the role of tumor necrosis factor receptor-associated factor 2 (Traf2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling. RESULTS:We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma tumor necrosis factor ? level was significantly elevated in Traf2-deficient mice, and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor ?-activated kinase 1 as a downstream effector. It is important to note that genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity. CONCLUSIONS:These results identify an important Traf2-mediated, NF?B-independent, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure.

Dataset Information

Casein kinase-1?1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3.

Publications

Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets