Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
复制标题
核糖体在硒蛋白翻译过程中的停滞暴露了铁下垂的脆弱性。
DOI：
10.1038/s41589-022-01033-3
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发表时间：
2022-07
影响因子：
14.8
通讯作者：
Olzmann, James A.
中科院分区：
文献类型：
--
作者：
Li, Zhipeng;Ferguson, Lucas;Deol, Kirandeep K.;Roberts, Melissa A.;Magtanong, Leslie;Hendricks, Joseph M.;Mousa, Gergey Alzaem;Kilinc, Seda;Schaefer, Kaitlin;Wells, James A.;Bassik, Michael C.;Goga, Andrei;Dixon, Scott J.;Ingolia, Nicholas T.;Olzmann, James A.
硒蛋白谷胱甘肽过氧化物酶4(Gpx4)通过将过氧化脂质转化为无毒的脂醇来预防铁下垂。Gpx4已成为一种很有前景的癌症治疗靶点，但一些癌细胞对由Gpx4抑制引起的铁下垂具有抵抗力。利用化学遗传筛选，我们确定LRP8(也称为ApoER2)是一种铁下垂抵抗因子，在癌症中上调。LRP8的缺失降低了细胞的硒水平和硒蛋白的表达。与经典的层次化硒蛋白调控程序相反，由于翻译受损，Gpx4水平显著降低。从机制上讲，低硒水平会导致低效解码的Gpx4硒半胱氨酸UGA密码子的核糖体停滞，导致核糖体碰撞，早期翻译终止，以及N端Gpx4片段的蛋白酶体清除。这些发现揭示了癌细胞中硒蛋白层次结构的重新连接，并确定Gpx4翻译过程中的核糖体停滞和碰撞是癌症中铁下垂的弱点。
The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into non-toxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Employing a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination, and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.8
作者：
Howard, Michael T.;Carlson, Bradley A.;Hatfield, Dolph L.
通讯作者：
Hatfield, Dolph L.
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Kim, DH;Iijima, H;Yamamoto, T
通讯作者：
Yamamoto, T
影响因子：
16
作者：
Juszkiewicz S;Chandrasekaran V;Lin Z;Kraatz S;Ramakrishnan V;Hegde RS
通讯作者：
Hegde RS