Research / Scientific departments / Cell Biology and Infection / Units and groups / Cell signaling and activation / Teams / Group 5 (R. Weil)
Group 5 (PI : Robert WEIL)
Optineurin, a multi-function protein
Antigen-induced NF-kB activation in T cells
The immune system includes two arms: the innate and the adaptive immunity. The former is the first line of defense against invading organisms and is referred to as a series of nonspecific defense mechanisms that are rapidly triggered upon viral or bacterial infection. The initiation of the adaptive immune response depends on the recognition of microbial or tumor-specific molecules by antigen receptors on the cell surface of lymphocytes. Antigen recognition leads to a variety of signaling events that result in dramatic changes in the expression of genes that control the activation, clonal proliferation and survival of the stimulated lymphocytes.
The nuclear factor (NF)- kB transcription factor participates in both innate and adaptive immunity through regulation of target genes encoding anti-apoptotic molecules, cell cycle regulators, cytokines and surface receptors. In normal unactivated cells, NF-kB proteins are sequestered in the cytoplasm through their interaction with the IkB inhibitors. Triggering of the T-cell antigen receptor or recognition of bacterial/viral products by Toll-like receptors present on the cell surface or in the endosomes leads to the activation of a cytoplasmic kinase complex formed of two catalytic (IKKa and IKKb) and one regulatory (NEMO) subunits, that induces phosphorylation, ubiquitination and subsequent degradation of IκB proteins. NF-kB dimers then translocate to the nucleus and activate their target genes.
Ubiquitination plays a crucial role in the NF-kB activation pathway. In particular, the role of K63-linked and linear polyubiquitin chains in NF-kB activation has been extensively studied.
NF-kB transcription factors can be uncoupled from their normal regulation and can promote tumorigenesis in different ways. For example, the Tax oncoprotein of human T cell leukemia virus (HTLV)-1 directly interacts with and constitutively activates the IKK complex, resulting in activation of NF-kB signaling pathway to promote tumorigenesis. A complex of proteins comprising Carma1, Bcl10 and Malt1 (CBM complex, Figure 1) plays key roles in the initiation of the adaptive immune response and mutations of their genes lead to dysregulation of the NF-kB activity. These mutations are associated with constitutive CBM-dependent signaling, and the development of particular subtypes of human B-cell lymphomas, such as mucosa-associated lymphoid tissue (MALT) and diffuse large B-cell (DLBCL) lymphomas (Lobry and Weil Med Sci 2007).
The NEMO/IkappaB kinase (IKK) complex is the central integrator of most stimuli leading to NF-κB activation, but the mechamisms leading to its regulation is not fully understood. Optineurin (Optn), a protein that presents structural homology with NEMO, can modulate NF-kB activation following the activation of NF-kB by TNFa or by the viral oncoprotein Tax. In addition to its NF-kB regulatory role, Optn has been suggested to be involved in a variety of functions (reviewed in Kachaner et al. Cell cycle 2012). Thus, a series of publications have focused on the role of Optn in Golgi organisation, membrane-trafficking events and protein secretion. Optn has also been involved in other pathways including protection against oxidative stress-induced apoptosis, regulation of agonist-stimulated Group I metabotropic glutamate receptors (mGluR1) signaling, cyst formation, regulation of endocytic trafficking of transferrin receptor and more recently in antiviral innate immune response and in selective autophagy of Salmonella enterica (Kachaner et al. Cell cycle 2012). Mutations within the Optn gene have been associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis, and genetic variants of Optn are also considered as genetic risk factors for Paget’s disease of bone. However, the molecular mechanism by which Optn mutations lead to these pathologies has not been established so far.
A first objective of our previous projects was to understand the molecular mechanisms that control the activation of NF-κB in physiological and pathological situations.- We have shown that degradation of the inhibitory protein IkBb is controlled by mechanisms that differ from those involved in the degradation of IkBa. In particular, the phosphorylation of IkBb, unlike that of IkBa, seems to be constitutive and independent of external stimuli (Weil et al. J Biol Chem 1997).
A second major aspect of our current research aims at uncovering the roles played by the protein Optn and to propose an integrated view of its functions (Kachaner et al., Cell cycle 2012)- We observed that Optn does not associate with the IKK kinases and unlike NEMO, which is cytosolic, is associated with the Golgi apparatus. We further demonstrated that its de novo expression is induced by interferon and TNF-a (Schwamborn, Weil et al. J Biol Chem 2000).
Robert Weil team includes 6 members :
Main current research projectsOur present work focuses on three axes:
Publications (since 1997)
R. Weil, C. Laurent Winter, and A. Israël. (1997) Regulation of IkBb degradation: similarities and differences with IkBa. J. Biol. Chem. 272: 9942-9949.
R. Weil, S. T. Whiteside, and A. Israël. (1997) Control of NF-κB activity by the IkBb inhibitor. Immunobiol. 197: 229-238.
H. Sirma, R. Weil, O. Rosmorduc, S. Urban, A. Israël, D. Kremsdorf, and C. Bréchot. (1998) Cytosol is the prime compartment of hepatitis B virus X protein where it associates with the proteasome. Oncogene. 16: 2051-2063.
R. Weil, J. P. Levraud, M. Duc Dodon, C. Bessia, U. Hazan, P. Kourilsky, and A. Israël. (1999) Altered expression and activity of tyrosine kinases of the Src and Syk families in HTLV-1-infected T cell lines. J. Virol. 73, 3709-3717.
R. Weil, H. Sirma, C. Giannini, D. Kremsdorf, C. Dargemont, C. Bréchot and A. Israël. (1999) Direct association and nuclear import of the hepatitis virus X protein with the NF-κB inhibitory protein IkBa. Mol. Cell. Biol..19, 6345-6354.
R. Eckenberg, T. Rose, J. L. Moreau, R. Weil, F. Gesbert, S. Dubois, D. Tello, M. Bossus, H. Gras, A. Tartar, J. Bertoglio, S. Chouaib, M. Goldberg, Y. Jacques, P. M. Alzari and J. These. (2000) The first alpha helix of interleukin (IL)-2 folds as a homotetramer, acts as an agonist of the IL-2 receptor beta chain, and induces lymphokine-activated killer cells. J. Exp Med. 191, 529-540.
C. Lobry, T. Lopez, A. Israël and R. Weil. Negative feed back loop in T-cell activation through IkB kinase-induced phosphorylation and degradation of Bcl10. (2007) Proc. Natl. Acad. Sci. 104 : 908-913. (Citations : N. R. Gough, Applying the Brakes to the Immune Response. Sci. STKE 2007, 370 : tw28. M. Hinz and C. Scheidereit. Striking back at the activator : how IkB kinase terminates antigen receptor responses. Sci. STKE 384 : pe19)
G. Despouy, M. Joiner, E. Le Toriellec, R. Weil and M. H. Stern. The Tcl1 oncoprotein inhibits activation-induced cell death by impairing PKC-q and Erk pathways (2007) Blood. 13 : 4406-4416.
R. Weil, and A. Israël. (2004) T-cell-receptor and B-cell-receptor-mediated NF-kappaB activation in lymphocytes. Current opinion in Immunology. 16 : 374-381.
R. Weil, and A. Israël. Deciphering the pathway from the TCR to NF-κB. (2006) Review in Cell Death and differentiation. 1-8.C. Lobry and R. Weil. New Bcl10 regulation mechanisms : a step in the comprehension of which has occured in MALT lymphomas ? (2007) Med. Sci. 23 : 11-13.
Etudiante en 3e année de thèse
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