STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1

Abstract

Tumor necrosis factor-alpha (TNF-α) exists in two forms: secretory TNF-α (sTNF-α) and transmembrane TNF-α (tmTNF-α). Although both forms of TNF-α induce tumor cell apoptosis, tmTNF-α is able to kill tumor cells that are resistant to sTNF-α-mediated cytotoxicity, indicating their differences in signal transduction. Here, we demonstrate that internalization of TNFR1 is crucial for sTNF-α- but not for tmTNF-α-induced apoptosis. sTNF-α induces binding of tumor necrosis factor receptor type 1-associated death domain protein (TRADD) to the death domain (DD) of TNFR1 and subsequent activation of nuclear factor kappa B (NF-κB), and the formation of death-inducing signaling complexes (DISCs) in the cytoplasm after internalization. In contrast, tmTNF-α induces DISC formation on the membrane in a DD-independent manner. It leads to the binding of signal transducer and activator of transcription 1 (STAT1) to a region spanning amino acids 319-337 of TNFR1 and induces phosphorylation of serine at 727 of STAT1. The phosphorylation of STAT1 promotes its binding to TRADD, and thus recruits Fas-associated protein with DD (FADD) and caspase 8 to form DISC complexes. This STAT1-dependent signaling results in apoptosis but not NF-κB activation. STAT1-deficiency in U3A cells counteracts tmTNF-α-induced DISC formation and apoptosis. Conversely, reconstitution of STAT1 expression restores tmTNF-α-induced apoptotic signaling in the cell line. Consistently, tmTNF-α suppresses the growth of STAT1-containing HT1080 tumors, but not of STAT1-deficient U3A tumors in vivo. Our data reveal an unappreciated molecular mechanism of tmTNF-α-induced apoptosis and may provide a new clue for cancer therapy.

The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis

“…Similarly, both TNF receptors are TACE substrates 38 . In addition, transmembrane TNF induces the formation of STAT1-dependent death-inducing signaling complexes (DISC) and apoptosis through its interaction with TNFR1 39 . These data suggest that MCJ deficiency contributes to disease severity at least partly due to the regulation of membrane TNF and its ability to signal through TNFR1.…”

Interleukin-35 Inhibits TNF-α-Induced Osteoclastogenesis and Promotes Apoptosis via Shifting the Activation From TNF Receptor-Associated Death Domain (TRADD)–TRAF2 to TRADD–Fas-Associated Death Domain by JAK1/STAT1

“…Wang et al previously reported that STAT1 can directly interact with TNFR1 and TRADD, as a component of the TNF-α receptor 1-TRADD signaling complex, to inhibit NF-κB activation ( 51 ). Jiang et al recently reported that the phosphorylation of STAT1 enhanced its binding to TRADD and thus recruits FADD and caspase 8 to form DISC complexes, resulting in apoptosis but not NF-κB activation ( 52 ).…”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…If NFκB activation is impaired, FADD and procaspase 8 attach to TNFR1-associated complex 1. As a result, caspase-8 is activated through limited proteolysis, and the process of apoptosis begins [20,21].…”