title: Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells.
abstract: 4-1BB is a member of the TNFR superfamily, which contributes to the activation of signaling pathways required for the survival of activated and memory T cells. We have shown previously that TRAF1, an adaptor protein recruited to 4-1BB, is required for 4-1BB-mediated CD8 T cell survival in vivo. With the use of a proteomics approach in primary T cells, we have identified LSP1 as a novel protein recruited to the 4-1BB signaling complex in a TRAF1-dependent manner. Further characterization of the interaction between TRAF1 and LSP1 revealed that LSP1 requires the TRAF-N domain of TRAF1 for direct association. Similarly to TRAF1(-/-) T cells, LSP1(-/-) T cells exhibit impaired ERK activation following stimulation through 4-1BB and consequently, are unable to down-modulate expression of the proapoptotic Bcl-2 family member Bim. Moreover, we demonstrate that the absence of LSP1 expression leads to defective expansion and survival of T cells in response to 4-1BB stimulation. Thus, we have identified LSP1 as a new mediator involved in 4-1BB signaling and T cell survival. Collectively, our work shows that TRAF1 and LSP1 cooperate downstream of 4-1BB to activate ERK signaling and down-modulate the levels of Bim leading to enhanced T cell survival.
authors: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada. laurent.sabbagh@umontreal.ca
authors: Laurent
authors: L
authors: Sabbagh
authors: Daniela
authors: D
authors: Andreeva
authors: Geneviève Dubeau
authors: GD
authors: Laramée
authors: N A Eustache
authors: NA
authors: Oussa
authors: Déborah
authors: D
authors: Lew
authors: Nicolas
authors: N
authors: Bisson
authors: Youssouf
authors: Y
authors: Soumounou
authors: Tony
authors: T
authors: Pawson
authors: Tania H
authors: TH
authors: Watts
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D000072224:Bcl-2-Like Protein 11; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D047990:TNF Receptor-Associated Factor 1 / Q000737:chemistry / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002135:Calcium-Binding Proteins; C057701:Lsp1 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048049:Extracellular Signal-Regulated MAP Kinases