Showing 23 results out of 105
The TRAFs (TRAF1 to TRAF6) are a group of structurally similar adaptor proteins, in most cases with E3 ligase activity, that are involved in downstream signaling of various cell surface receptors such as TNFR1, TNFR2, CD40, TLRs and TCR (Jang HD et al. 2001; Fotin-Mleczek M et al. 2004; Su X et al. 2006). The hallmark feature of all TRAFs is a C-terminal TRAF-domain of approximately 230 amino acids, which is responsible for homo- and heterooligomerization of TRAF molecules (Rothe M et al. 1994). The differences in amino acid sequences in TRAF-domains define the range of TRAF interaction partners. Another important structural element of TRAFs, with an exception of TRAF1, is the N-terminal RING finger domain that modulates induction of NFkappaB and MAPK activities. As TRAF1 has no RING finger domain, the effects of TRAF1 on NFkB activation are rather unclear. It is believed that TRAF1 regulates TNF receptor activity through its ability to interact with TRAF2 (Rothe M et al.1995; Zheng C et al. 2010; Fotin-Mleczek M et al. 2004). Structural and biochemical studies showed that TRAF1:TRAF2 heterotrimer (1:2) binds BIRC (cIAP2) more strongly than TRAF2 homotrimers, suggesting that TRAF1 may modulate the interaction between TRAF2 and BIRC (cIAP1/2) and thus suppress TNF-alpha induced apoptosis (Zheng C et al. 2010). Noteworthy, TRAF1:TRAF2 heterotrimers and TRAF2 homotrimers also differ in their capability with certain receptors but there seems to be no difference with respect to TNFR1 recruitment (Fotin-Mleczek M et al. 2004). On the contrary, TNF-induced caspase-mediated cleavage of TRAF1 generates a C-terminal fragment with NFkB-inhibitory, pro-apoptotic activity (Leo e et al. 2001; Jang HD et al. 2001; Henkler F et al. 2003). Thus, the current data suggest that depending on its cleavage status TRAF1 may exert either cytoprotective or cytotoxic effect in death domain-containing receptor signaling pathways.
The heteromeric complex TRAF1:TRAF2 has been also implicated in the cross-talk of TNFR1 and TNFR2 (Wicovsky A et al. 2009).
The binding of TNF-alpha to TNFR1 leads to recruitment of the adapter protein TNFR1-associated death domain (TRADD) and of receptor‑interacting protein 1 (RIPK1). TRADD subsequently recruits also TNF receptor-associated factor 2 (TRAF2). RIPK1 is promptly K63-polyubiquitinated which results in the recruitment of the TAB2:TAK1 complex and the IkB kinase (IKK) complex to TNFR1. The activated IKK complex mediates phosphorylation of the inhibitor of NFkappaB (IkB), which targets IkB for ubiquitination and subsequent degradation. Released NFkappaB induces the expression of a variety of genes including inflammation-related genes and anti-apoptotic genes encoding proteins such as inhibitor of apoptosis proteins cIAP1/2, Bcl-2, Bcl-xL or cellular FLICE-like inhibitory protein (FLIP) (Blonska M et al. 2005; Ea CK et al. 2006; Wu CJ et al. 2006; Chen C et al. 2000; Manna SK et al. 2000; Kreuz S et al. 2001; Micheau O et al. 2001). NFkB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. However, as caspases activate JNK quite efficiently, JNKs are also regularly stimulated in course of apoptosis without being essential for cell death (Wicovsky A et al. 2007). AP1-mediated gene induction results from activation of JNK via TRAF2 (not shown here) (Tsou HK et al. 2012). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced by internalization-associated fashion upon the release of RIPK1 from the membrane complex (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004; Tchikov V et al. 2011).
TNFR1-mediated transcriptional activity of NFkB is both antiapoptotic and highly proinflammatory and thus must be tightly regulated to prevent constitutive activation that leads to persistent inflammation and cancer (Ward C et al. 1999; Fujihara S et al. 2002; Pekalski J et al. 2013; Kankaanranta H et al. 2014; Shukla S and Gupta S 2004; Jackson-Bernitsas DG et al. 2007; Zhang JY et al. 2007). Multiple mechanisms normally ensure the proper control of NFkappaB activation including two negative feedback loops mediated by NFkappaB inducible inhibitors, IkB-alpha (NFKBIA) and ubiquitin-editing protein A20 (He KL & Ting AT 2002; Wertz IE et al. 2004; Vereecke L et al. 2009; Pekalski J et al. 2013).