Dataset Information

CIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand.

ABSTRACT: Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types, including macrophages, dendritic cells, and osteoclasts. We have described the migration of cellular inhibitor of apoptosis protein 1 (cIAP1), a member of the IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) by the proteosomal machinery. Inhibition of cIAP1 prevents the decrease in TRAF2 expression that characterizes macrophage formation. We demonstrate that TRAF2 is initially required for macrophage differentiation as its silencing prevents Ikappa-Balpha degradation, nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation, and the differentiation process. Then, we show that cIAP1-mediated degradation of TRAF2 allows the differentiation process to progress. This degradation is required for the macrophages to be fully functional as TRAF2 overexpression in differentiated cells decreases the c-Jun N-terminal kinase-mediated synthesis and the secretion of proinflammatory cytokines, such as interleukin-8 and monocyte chemoattractant protein 1 (MCP-1) in response to CD40 ligand. We conclude that TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages.

SUBMITTER: Dupoux A

PROVIDER: S-EPMC2951832 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand.

Dupoux Alban A Cartier Jessy J Cathelin Séverine S Filomenko Rodolphe R Solary Eric E Dubrez-Daloz Laurence L

Blood 20080930 1

Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types, including macrophages, dendritic cells, and osteoclasts. We have described the migration of cellular inhibitor of apoptosis protein 1 (cIAP1), a member of the IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein tumor ...[more]

PMID: 18827186

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Project description:The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients and growth factors, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling. Although both mTOR and G?L (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11, 12, 13, 14, 15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of G?L dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of G?L, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12, 13, 14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from G?L to promote G?L interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in G?L, by either K305R/K313R mutations or a melanoma-associated G?L(?W297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a G?L-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.

Dataset Information

CIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand.

Publications

cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand.

Similar Datasets

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