Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma.
Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma.
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DOI：
10.3324/haematol.2019.234385
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发表时间：
2021-02-01
期刊：
影响因子：
10.1
通讯作者：
Gandhi V
中科院分区：
文献类型：
--
作者：
Sarkar A;Stellrecht CM;Vangapandu HV;Ayres M;Kaipparettu BA;Park JH;Balakrishnan K;Burks JK;Pandita TK;Hittelman WN;Neelapu SS;Gandhi V
共济失调性毛细血管扩张症突变（ATM）是一种具有蛋白激酶活性的关键DNA损伤传感器，在包括套细胞淋巴瘤在内的人类癌症中经常发生改变。ATM蛋白的丢失与小鼠胸腺细胞和共济失调毛细血管扩张细胞中非功能性线粒体的积累和线粒体自噬缺陷有关。然而，ATM激酶在癌细胞线粒体自噬中的机制作用尚不清楚。在这里，我们提供的证据表明，FCCP诱导的线粒体自噬在套细胞淋巴瘤和其他癌细胞系是依赖于ATM，但独立于其激酶功能。虽然Granta-519套细胞淋巴瘤细胞具有单拷贝激酶死亡的ATM并且对FCCP诱导的线粒体自噬具有抗性，但Jeko-1和Mino细胞都是ATM熟练的并且诱导线粒体自噬。在Jeko-1和Mino细胞中稳定敲除ATM赋予对线粒体自噬的抗性，并且与ATP产生减少、氧消耗减少和线粒体活性氧增加相关。ATM与E3泛素连接酶Parkin以激酶非依赖性方式相互作用。在HeLa细胞中敲除ATM导致GFP-帕金蛋白的蛋白酶体降解，其被蛋白酶体抑制剂MG 132拯救，这表明ATMParkin相互作用对于帕金稳定性是重要的。原发性B细胞淋巴瘤中ATM激酶活性的丧失和套细胞淋巴瘤、共济失调毛细血管扩张症和HeLa细胞系中ATM激酶的抑制都不能减轻FCCP或CCCP诱导的线粒体自噬，这表明ATM激酶活性与线粒体自噬无关。未检测到ATM、Parkin、Pink 1和Parkin-UbSer 65磷酸化的恶性B细胞淋巴瘤对线粒体自噬具有抗性，这为ATM在套细胞淋巴瘤和其他B细胞淋巴瘤中线粒体自噬的作用提供了第一个分子证据。
Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, is frequently altered in human cancers including mantle cell lymphoma. Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy in both murine thymocytes and in ataxia-telangiectasia cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in mantle cell lymphoma and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 mantle cell lymphoma cells possess single copy kinase-dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATMproficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mitochondrial reactive oxygen species. ATM interacts with the E3 ubiquitin ligase Parkin in a kinase-independent manner. Knockdown of ATM in HeLa cells resulted in proteasomal degradation of GFP-Parkin which was rescued by the proteasome inhibitor, MG132, suggesting that the ATMParkin interaction is important for Parkin stability. Neither loss of ATM kinase activity in primary B-cell lymphomas nor inhibition of ATM kinase in mantle cell lymphoma, ataxia-telangiectasia and HeLa cell lines mitigated FCCP- or CCCP-induced mitophagy suggesting that ATM kinase activity is dispensable for mitophagy. Malignant B-cell lymphomas without detectable ATM, Parkin, Pink1, and Parkin-UbSer65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of the role of ATM in mitophagy in mantle cell lymphoma and other B-cell lymphomas.
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影响因子：
13.8
作者：
Ditch, Scott;Paull, Tanya T.
通讯作者：
Paull, Tanya T.
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Narendra D;Tanaka A;Suen DF;Youle RJ
通讯作者：
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影响因子：
14.8
作者：
Kang, Hyun Tae;Park, Joon Tae;Park, Sang Chul
通讯作者：
Park, Sang Chul
影响因子：
4.8
作者：
Pawlyk, AC;Giasson, BI;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
11.4
作者：
Chaugule, Viduth K.;Burchell, Lynn;Walden, Helen
通讯作者：
Walden, Helen