IFN-γ Induces Mimic Extracellular Trap Cell Death in Lung Epithelial Cells Through Autophagy-Regulated DNA Damage

Area of Science:

• Oncology
• Cell Biology
• Immunology

Background:

• Interferon-γ (IFN-γ) is known to inhibit cell growth and cause cytotoxicity in lung epithelial malignancies.
• The role of autophagy in IFN-γ signaling and its contribution to cytotoxicity remains an area of investigation.

Purpose of the Study:

• To investigate the intricate link between autophagy and IFN-γ-induced cytotoxicity in lung cancer.
• To elucidate the mechanisms underlying IFN-γ-mediated cell death, including nonapoptotic pathways.

Main Methods:

• Treatment of A549 and PC14PE6/AS2 human lung cancer cells with IFN-γ.
• Analysis of apoptotic and nonapoptotic cell death pathways.
• Investigation of autophagy induction, caspase activation, DNA damage, and histone citrullination.

Main Results:

• IFN-γ treatment induced both apoptotic and nonapoptotic cell death in A549 cells.
• Nonapoptotic cell death mimicked extracellular trap cell death (ETosis), regulated by caspase-3, autophagy, and immunity-related GTPase family M protein 1 (IRGM1) and activating transcription factor 6 (ATF6).
• IFN-γ signaling controlled mimic ETosis via autophagy- and Fas-associated protein with death domain (FADD)-mediated caspase-8/-3 activation, leading to DNA damage and ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM)-regulated peptidyl arginine deiminase 4 (PAD4)-mediated histone citrullination.
• These effects were impaired in PC14PE6/AS2 cells resistant to IFN-γ-induced autophagy.

Conclusions:

• IFN-γ triggers unconventional, autophagy-based caspase cascade activation leading to DNA damage in lung epithelial malignancies.
• This process culminates in ATR/ATM-regulated PAD4-mediated histone citrullination during mimic ETosis.
• Understanding this pathway provides novel insights into IFN-γ's cytotoxic mechanisms and potential therapeutic strategies.