p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis

Abstract

The autophagy–lysosome pathway and apoptosis constitute vital determinants of cell fate and engage in a complex interplay in both physiological and pathological conditions. Central to this interplay is the archetypal autophagic cargo adaptor p62/SQSTM1/Sequestosome-1 which mediates both cell survival and endoplasmic reticulum stress-induced apoptosis via aggregation of ubiquitinated caspase-8. Here, we investigated the role of p62-mediated apoptosis in head and neck squamous cell carcinoma (HNSCC), which can be divided into two groups based on human papillomavirus (HPV) infection status. We show that increased autophagic flux and defective apoptosis are associated with radioresistance in HPV(-) HNSCC, whereas HPV(+) HNSCC fail to induce autophagic flux and readily undergo apoptotic cell death upon radiation treatments. The degree of radioresistance and tumor progression of HPV(-) HNSCC respectively correlated with autophagic activity and cytosolic levels of p62. Pharmacological activation of the p62-ZZ domain using small molecule ligands sensitized radioresistant HPV(-) HNSCC cells to ionizing radiation by facilitating p62 self-polymerization and sequestration of cargoes leading to apoptosis. The self-polymerizing activity of p62 was identified as the essential mechanism by which ubiquitinated caspase-8 is sequestered into aggresome-like structures, without which irradiation fails to induce apoptosis in HNSCC. Our results suggest that harnessing p62-dependent sequestration of ubiquitinated caspase-8 provides a novel therapeutic avenue in patients with radioresistant tumors.

The dual role of autophagy in HPV-positive head and neck squamous cell carcinoma: a systematic review

“…Lee et al ( 2021 ) and Cho et al ( 2021 ) were investigating the interplay between p62/SQSTM1 (Sequestosome 1) and HPV16 in HNSCC. Based on their experiments, Lee et al concluded that upon radiation treatments HPV16 + HNSCC cells fail to induce autophagic LC3 flux, as assessed by LC3B western blotting in cells that had been treated with Bafilomycin A1, and undergo apoptotic cell death (Lee et al 2021 ). Immunoblotting analyses showed no obvious difference in the expression level of p62 between HPV − and HPV16 + cell lines.…”

NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer

“…In head & neck squamous cell carcinoma cells, the autophagic cargo adapter p62/SQSTM1 is augmenting the activation and full processing of caspase 8 by capturing ubiquitinated caspase 8 into aggresome-like structures, necessary for subsequent apoptosis induction upon radiation treatment [ 22 ]. These findings raised the question if p62 is part of the apoptosis-inducing signaling pathway which is affected by A20 in TRAIL-resistant PDAC cells.…”

Dehydroepiandrosterone exacerbates nigericin-induced abnormal autophagy and pyroptosis via GPER activation in LPS-primed macrophages

“…6D ). According to reports, the protein p62 was shown to activate caspase-8 [ 37 , 38 ]; and activated caspase-8 can cleave GSDMD to promote cell pyroptosis [ 39 , 40 ]. Thus, these results confirmed that DHEA exacerbates Nig-induced pyroptosis in LPS-primed macrophages via GPER activation, and the DHEA-caused pyroptosis may be related to p62-caspase-8-GSDMD pathway.…”