STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy
STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy
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DOI：
10.4161/auto.25190
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发表时间：
2013-09-01
期刊：
影响因子：
13.3
通讯作者：
Pereira, Paulo
中科院分区：
文献类型：
--
作者：
Ferreira, Joao Vasco;Fofo, Hugo;Pereira, Paulo
转录因子 HIF1 主要受不稳定亚基 HIF1A 的氧依赖性蛋白酶体降解的调节。最近的数据显示 HIF1A 在溶酶体中通过分子伴侣介导的自噬 (CMA) 降解。然而所涉及的分子机制尚未阐明。这项研究表明，在所有 CMA 底物中都已发现的 KFERQ 样基序是介导 HIF1A 和分子伴侣 HSPA8 之间相互作用所必需的。此外，HIF1A 的 KFERQ 样基序的突变阻止了与 CMA 受体 LAMP2A 的相互作用，从而抑制其溶酶体降解。重要的是，我们首次证明 CMA 降解溶酶体中的 HIF1A 需要泛素连接酶 STUB1。事实上，STUB1 中的突变会抑制泛素连接酶活性或其与 HSPA8 结合的能力，从而阻止 CMA 降解 HIF1A。此外，我们发现 HIF1A 与从大鼠肝脏分离的完整溶酶体结合并易位到其中。这种新的 HIF1A 降解途径不依赖于氧气的存在，并且在营养剥夺时被激活，因此在饥饿动物肝脏中与 CMA 阳性溶酶体结合的 HIF1A 水平显着增加，并且在血清剥夺时 HIF1A 与 LAMP2A 的结合增加。此外，CMA 对 HIF1A 的过度降解会损害细胞在缺氧下的反应和生存能力，这表明该途径在缺氧和饥饿相结合的条件下可能具有病理生理学重要性。
The transcription factor HIF1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit HIF1A. Recent data showed degradation of HIF1A in the lysosome through chaperone-mediated autophagy (CMA). However the molecular mechanism involved has not been elucidated. This study shows that the KFERQ-like motif, that has been identified in all CMA substrates, is required to mediate the interaction between HIF1A and the chaperone HSPA8. Moreover, mutations in the KFERQ-like motif of HIF1A preclude the interaction with the CMA receptor LAMP2A, thus inhibiting its lysosomal degradation. Importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of HIF1A in the lysosome by CMA. Indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to HSPA8, both prevent degradation of HIF1A by CMA. Moreover, we show that HIF1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of HIF1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of HIF1A bound to CMA positive lysosomes significantly increase in starved animal livers and the binding of HIF1A to LAMP2A increases in response to serum deprivation. Moreover, excessive degradation of HIF1A by CMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation.