Dataset Information

Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.

ABSTRACT: The physiological activity of Notch is a function of its ability to increase survival in many cell types. Several pathways have been shown to contribute to the survival effect of Notch, but the exact mechanism of Notch action is not completely understood. Here we identified that the regulation of cell survival by Notch intracellular domain could partly be attributed to a selective increase of X-linked inhibitor of apoptosis protein (XIAP). We further found that Notch intracellular domain inhibited the degradation of XIAP during apoptosis. The transactivation domain of Notch interacted directly with the RING region of XIAP to block the binding of E2 and prevent the in vivo and in vitro ubiquitination of XIAP. This antiapoptotic activity of Notch was abolished when XIAP was knocked down. Our results reveal a novel mechanism for Notch-selective suppression of apoptosis through an increase in the stability of a key antiapoptotic protein, XIAP.

SUBMITTER: Liu WH

PROVIDER: S-EPMC1829378 | biostudies-other | 2007 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.

Liu Wen-Hsien WH Hsiao Huey-Wen HW Tsou Wen-I WI Lai Ming-Zong MZ

The EMBO journal 20070222 6

The physiological activity of Notch is a function of its ability to increase survival in many cell types. Several pathways have been shown to contribute to the survival effect of Notch, but the exact mechanism of Notch action is not completely understood. Here we identified that the regulation of cell survival by Notch intracellular domain could partly be attributed to a selective increase of X-linked inhibitor of apoptosis protein (XIAP). We further found that Notch intracellular domain inhibit ...[more]

PMID: 17318174

Similar Datasets

Project description:Ehrlichia chaffeensis has evolved multiple strategies to evade innate defenses of the mononuclear phagocyte. Recently, we reported the E. chaffeensis tandem repeat protein (TRP)120 effector functions as a Notch ligand mimetic and a ubiquitin ligase that degrades the nuclear tumor suppressor, F-box and WD repeat domain-containing 7, a negative regulator of Notch. The Notch intracellular domain (NICD) is known to inhibit apoptosis primarily by interacting with X-linked inhibitor of apoptosis protein (XIAP) to prevent degradation. In this study, we determined that E. chaffeensis activation of Notch signaling increases XIAP levels, thereby inhibiting apoptosis through both the intrinsic and executioner pathways. Increased NICD and XIAP levels were detected during E. chaffeensis infection and after TRP120 Notch ligand mimetic peptide treatment. Conversely, XIAP levels were reduced in the presence of Notch inhibitor DAPT. Cytoplasmic and nuclear colocalization of NICD and XIAP was observed during infection and a direct interaction was confirmed by co-immunoprecipitation. Procaspase levels increased temporally during infection, consistent with increased XIAP levels; however, knockdown (KD) of XIAP during infection significantly increased apoptosis and Caspase-3, -7, and -9 levels. Furthermore, treatment with SM-164, a second mitochondrial activator of caspases (Smac/DIABLO) antagonist, resulted in decreased procaspase levels and increased caspase activation, induced apoptosis, and significantly decreased infection. In addition, RNAi KD of XIAP also decreased infection and significantly increased apoptosis. Moreover, ectopic expression of TRP120 HECT Ub ligase catalytically defective mutant in HeLa cells decreased NICD and XIAP levels and increased caspase activation compared to HeLa cells with functional HECT Ub ligase catalytic activity (TRP120-WT). This investigation reveals a mechanism whereby E. chaffeensis modulates Notch signaling to stabilize XIAP and inhibit apoptosis.

Dataset Information

Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.

Publications

Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets