Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Abstract

Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

“…Subsequently ISGF3 will migrate to the nucleus, bind to IFN-stimulated response element (ISRE) sequences, and initiate the transcription of several ISGs6. In addition to its anti-viral roles, IFN-I is also known to be associated with several additional biological functions such as cell proliferation, adaptive immune cell homeostasis, immune adjuvant, endotoxin shock78910.…”

NAD+prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

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Macrophage response to oncolytic paramyxoviruses potentiates virus‐mediated tumor cell killing

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