Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

Abstract

The regulation of cellular survival and apoptosis is of critical importance for the immune system to maintain immune homeostasis and to establish tolerance. Here, we demonstrate that the immune specific cell surface molecule Toso exhibits antiapoptotic effects on death receptor signaling by a novel regulatory mechanism involving the adaptor kinase RIP1.The antiapoptotic function of Toso depends on RIP1 ubiquitination and involves the recruitment of the death adaptor FADD to a Toso/RIP1 protein complex. In response to CD95L and TNF␣, Toso promotes the activation of MAPK and NF-B signaling pathways. Because of this relative augmentation of survival versus apoptotic signals, Toso raises the threshold for death receptormediated apoptosis. Our analysis of Tosodeficient mice revealed that Toso is essential for TNF␣-mediated liver damage. Furthermore, the antiapoptotic function of Toso could be blocked by a Toso-specific monoclonal antibody, opening up new therapeutic prospects for the treatment of immune disorders and hematologic malignancies. (Blood. 2011;118(3):598-608) IntroductionOne of the most well-characterized death receptors in the immune system is CD95 (Fas, APO-1). CD95 belongs to the TNF receptor superfamily. Expressed as preassociated homotrimers, CD95 on ligand binding directly conveys apoptotic signals. On ligand binding, CD95 assembles the death inducing signaling complex (DISC). The DISC consists of the death adaptor FADD (Fas associated death domain protein), procaspase-8, and procaspase-10. 1,2 Efficient DISC formation provides a molecular scaffold concentrating cysteine proteases to induce autoproteolytic cleavage of caspase-8 and release of active caspase-8 that initiates the apoptotic program. Mutations of CD95 or its ligand have been found in autoimmune strains of mice and in patients with autoimmune lymphoproliferative syndrome (ALPS). 3 These genetic abnormalities in CD95 result in the development of massive lymphoadenopathy and disruption of lymphocyte homeostasis because of increased survival of activated lymphocytes. 4,5 Although CD95 has been mainly perceived as a death inducing receptor, recent findings paint a far more complex picture of CD95 and the DISC components by providing evidence that they can transmit both, deathinducing and cellular activation signals in response to the same ligand. 6,7 Such nonapoptotic signaling activities of CD95 are thought to mediate proinflammatory responses in immune cells, neuronal tissue remodeling and promote tumor progression. [7][8][9] The execution and regulation of CD95-mediated nonapoptotic signaling, in particular with respect to its contribution to tumorigenesis, is however still largely unclear.Toso, also known as FAIM3, is a type I transmembrane protein belonging to the immunoglobulin gene superfamily. Toso was originally identified as a surface molecule with negative regulatory function on lymphocyte apoptosis. 10 Recent studies have also implicated Toso in IgM binding. 11 The expression of Toso is restricted to lymphoid organs, where it is ...

Involvement of Toso in activation of monocytes, macrophages, and granulocytes

“…S1. We then analyzed Toso expression on bone marrow-derived granulocytes from WT and Toso −/− animals using a Toso-specific antibody (7). Immature (Ly6G med ) and mature (Ly6G hi ) granulocytes from WT bone marrow exhibited expression of Toso (Fig.…”

“…Toso −/− mice were backcrossed into the C57BL/6 background for more than nine generations before use in experiments. Toso del/del mice, an independent line of Toso KO mice on the C57BL/6 background, have been previously described (7). sIgM −/− mice were also maintained on the C57BL/6 genetic background.…”

“…Mechanistically, Toso was originally described to influence Fas signaling (1, 5). We previously reported that TNF-induced apoptosis is enhanced in the absence of Toso (6,7). Other work has shown that Toso can act as an Fc receptor for IgM (8,9) and is important for the phagocytosis of IgM-coated targets (10).…”

Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

“…In humans, FcμR was found to be expressed by B cells, T cells, and natural killer cells (16), and it is possible that human FcμR may have additional functions not present in mice. In fact, FcμR has been suggested to regulate Fas-mediated apoptosis in human T and B cells (23,24).…”

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

“…Thus, the extrinsic pathway is inhibited by Faim3, IEX-1, and TRAF5 (25)(26)(27). For Faim3, this may involve inhibition of caspase 8 recruitment and diversion of Fas/CD95 signaling toward survival pathways (37). On the other hand, Bcl-2, Bcl-3, and β-arrestin inhibit the intrinsic apoptosis pathway by preventing Bax/Bak multimerization, release of Bim and inducing expression of the Bcl2 gene, respectively (3,6,21,24,38).…”