TNFR1 signaling pathways

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TNF-α exerts its effects by binding to two receptors, TNFR1 and TNFR2 [16]. Recently, progranulin was identified as a ligand of TNFR with a higher affinity than TNF-α. Progranulin antagonizes TNF-α signaling and plays a critical role in the pathogenesis of inflammatory arthritis in mice [23]. TNFR1, a 55 kDa protein with a DD in its intracellular region, is expressed in almost all cell types, whereas, TNFR2, a 75 kDa protein, is mainly expressed in oligodendrocytes, astrocytes, T cells, myocytes, thymocytes, endothelial cells, and human mesenchymal stem cells [24]. Considerable uncertainty persists regarding the TNFR2 signaling pathway, which has been reviewed previously [24]. The CRD1 domains of CD95, TNFR1, and TNFR2 are involved in homotypic interactions, leading to pre-association of the receptor as a homotrimer in the absence of ligand [19, 20, 25]. Thus, this domain has been designated the pre-ligand binding assembly domain (PLAD) [25]. Receptors of the TNFR superfamily do not possess any enzymatic activity on their own, and therefore rely on the recruitment of adaptor proteins for signaling. Among these adaptor proteins, TRADD or FADD are instrumental in the implementation of cell death processes [3-6].

TNF-α is synthesized as a 26 kDa transmembrane type II protein (m-TNF-α) of 233 amino acids [26], which can be cleaved by the metalloprotease TACE [27, 28] to release the 17 kDa soluble form of the cytokine (cl-TNF-α). In contrast to cl-TNF-α, which only activates TNFR1, m-TNF-α can bind and activate both TNFR1 and TNFR2 [29].

Activation of TNFR1 induces cellular processes ranging from cell death (apoptosis or necroptosis) to cell proliferation, migration, and differentiation; the implementation of these cellular responses reflects the formation of different molecular complexes following receptor activation [24]. Binding of TNF to TNFR1 causes formation of two consecutive complexes, resulting in the divergence of their kinetic and spatial distributions. Whereas the plasma membrane complex (complex I) elicits a non-apoptotic signaling pathway, a second, internalized complex (complex II or DISC) triggers cell death [30]. In the presence of TNF-α, the adaptor protein TRADD interacts with TNFR1 and recruits other proteins involved in the signaling of the receptor, such as TRAF2, cIAP1, cIAP2, and RIP1, to form complex I. At the plasma membrane, this complex activates the NF-κB signaling pathway, which in turn promotes transcription of anti-apoptotic genes such as cIAP-1, cIAP-2, and c-FLIP [31]. The linear ubiquitin chain assembly complex (LUBAC) is also recruited to complex I via cIAP-generated ubiquitin chains [32]. The LUBAC complex consists of HOIL-1, HOIP, and sharpin; HOIL-1 and HOIP add a linear ubiquitin chain by catalyzing the head-to-tail ligation of ubiquitin [33] to RIP1 and NEMO (IKKγ) in complex I [34], thereby activating NF-κB.

TNF-α–induced caspase activation is mediated by a second intracellular complex, known as complex II, which is formed when complex I dissociates from the receptor along with FADD and caspase-8 recruitment [30]. NF-κB activation leads to c-FLIP overexpression, preventing formation of complex II. Contrariwise, when NF-κB activation is blocked, the short-lived c-FLIP protein is depleted [35], and cells undergo programmed death [30]. In this context, RIP1 is deubiquitinated by enzymes such as Cezanne [36] and CYLD [37]. In addition, the complex composed of TRADD and RIP1 moves to the cytosol to form complex II. FADD is recruited to TRADD by the DD–DD interaction and binds caspase-8 [30]. Notably, when caspase-8 activity is inhibited or its expression is extinguished, DISC is unable to trigger the apoptotic signaling pathway, but TNFR1 or CD95 stimulation leads to the activation of another cell death signal, necroptosis [38, 39]. To prevent the induction of the necroptotic signal, caspase-8 cleaves and inactivates RIP1 and RIP3 [40]. The fine-tuned control of necroptosis by members of the apoptotic signaling pathway has been elegantly confirmed by experiments showing that the embryonic lethality of mice harboring single KO of caspase-8 or FADD can be rescued by an additional KO of the RIP3 gene [41-43].