Cellular Inhibitors of Apoptosis Are Global Regulators of NF-κB and MAPK Activation by Members of the TNF Family of Receptors

Abstract

Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c-IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-κB and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of κB kinase β (IKKβ), the IKK regulatory subunit NF-κB essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-κB pathway triggered translocation of c-IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell-activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-κB activation. These results define c-IAP proteins as critical regulators of the activation of NF-κB and MAPK signaling pathways by members of the TNFR superfamily.

RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

“…Here, we show these effects in tumor cell lines and that a TWEAK blockade with an anti-TWEAK mAb, RG7212, results in significant tumor growth inhibition (TGI) in multiple tumor models expressing Fn14. These in vitro and in vivo data are consistent with tumor-promoting effects shown with other TNF family receptors lacking death domains (19,20) and with TWEAK data in disease models in animals and pathologic conditions in humans (21,22).…”

Deubiquitinases in skeletal muscle atrophy

“…Previous studies in HEK293 cells have shown that USP19 can deubiquitinate and stabilize cIAP proteins (Mei et al, 2011). These proteins can promote TNFα signaling in several cell types (Varfolomeev et al, 2012) and can also inhibit myogenesis in primary muscle cells (Enwere et al, 2012). So an attractive hypothesis is that USP19 might promote muscle atrophy by stabilizing cIAPs and activating the NFκB pathway.…”

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

“…11,[26][27][28] Apart from these chemicals, a set of biological ligand of the TNF family, such as lymphotoxin LTα 1 β 2 , CD40L or Tweak, also appeared to target c-IAP1/2 toward the proteasomal and/ or lysosomal degradative pathways. [29][30][31][32][33][34] c-IAP1/2 depletion leads to NIK (NF-κB-inducing kinase) stabilization and the phosphorylation of both IKKα and NF-κB2/p100 prior to the processing of p100 into p52, a pathway defined as the alternative, or non-canonical, NF-κB pathway. [35][36][37] Genetic mouse models revealed that NIK is required for the proper development and/or maintenance of secondary lymphoid organs, for osteoclastogenesis, for T-cell activation as well for B-cell survival.…”