p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis.
p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis.
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DOI：
10.1038/s41419-021-04301-7
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发表时间：
2021-10-25
影响因子：
9
通讯作者：
Kim HC
中科院分区：
文献类型：
--
作者：
Lee SH;Cho WJ;Najy AJ;Saliganan AD;Pham T;Rakowski J;Loughery B;Ji CH;Sakr W;Kim S;Kato I;Chung WK;Kim HE;Kwon YT;Kim HC
自噬-溶酶体途径和细胞凋亡构成细胞命运的重要决定因素，并在生理和病理条件下参与复杂的相互作用。这种相互作用的核心是原型自噬货物衔接子p62/SQSTM 1/Sequestosome-1，其通过泛素化caspase-8的聚集介导细胞存活和内质网应激诱导的凋亡。在这里，我们研究了p62介导的细胞凋亡在头颈部鳞状细胞癌（HNSCC）中的作用，根据人乳头瘤病毒（HPV）感染状态，HNSCC可分为两组。我们发现，自噬通量增加和凋亡缺陷与HPV（-）HNSCC的放射抗性相关，而HPV（+）HNSCC不能诱导自噬通量，并容易在放射治疗后发生凋亡性细胞死亡。HPV（-）HNSCC的放射抵抗程度和肿瘤进展分别与自噬活性和胞浆p62水平相关。使用小分子配体的p62-ZZ结构域的药理学活化通过促进p62自聚合和货物的隔离导致细胞凋亡而使辐射抗性HPV（-）HNSCC细胞对电离辐射敏感。p62的自聚合活性被确定为泛素化的caspase-8被隔离到侵袭体样结构中的基本机制，没有该机制，照射不能诱导HNSCC中的凋亡。我们的研究结果表明，利用p62依赖性螯合泛素化caspase-8提供了一种新的治疗途径，在放射抵抗性肿瘤患者。
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.
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影响因子：
--
作者：
Jung YS;Najy AJ;Huang W;Sethi S;Snyder M;Sakr W;Dyson G;Hüttemann M;Lee I;Ali-Fehmi R;Franceschi S;Struijk L;Kim HE;Kato I;Kim HC
通讯作者：
Kim HC
影响因子：
5.2
作者：
Cho WJ;Kessel D;Rakowski J;Loughery B;Najy AJ;Pham T;Kim S;Kwon YT;Kato I;Kim HE;Kim HC
通讯作者：
Kim HC
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
64.5
作者：
Jin, Zhaoyu;Li, Yun;Ashkenazi, Avi
通讯作者：
Ashkenazi, Avi
影响因子：
21.3
作者：
Cha-Molstad, Hyunjoo;Sung, Ki Sa;Hwang, Joonsung;Kim, Kyoung A.;Yu, Ji Eun;Yoo, Young Dong;Jang, Jun Min;Han, Dong Hoon;Molstad, Michael;Kim, Jung Gi;Lee, Yoon Jee;Zakrzewska, Adriana;Kim, Su-Hyeon;Kim, Sung Tae;Kim, Sun Yong;Lee, Hee Gu;Soung, Nak Kyun;Ahn, Jong Seog;Ciechanover, Aaron;Kim, Bo Yeon;Kwon, Yong Tae
通讯作者：
Kwon, Yong Tae