Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation
Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation
复制标题
DOI：
10.1074/jbc.m112.414771
复制
发表时间：
2013-04-12
影响因子：
4.8
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Hubbi, Maimon E.;Hu, Hongxia;Semenza, Gregg L.
缺氧诱导因子-1（HIF-1）是一种异源二聚体转录因子，介导对缺氧的适应性反应。我们证明了由分子伴侣介导的自噬（CMA）引起的HIF-1 α亚基的溶酶体降解是HIF-1活性的主要调节因子。溶酶体降解的药理学抑制剂，如巴弗洛霉素和氯喹，增加HIF-1 α水平和HIF-1活性，而伴侣介导的自噬的激活剂，包括6-氨基烟酰胺和营养饥饿，降低HIF-1 α水平和HIF-1活性。相比之下，大自噬抑制剂不增加HIF-1活性。转录因子EB是溶酶体生物发生的主要调节因子，也负调节HIF-1活性。HIF-1 α与HSC 70和LAMP 2A相互作用，这是CMA机制的核心组成部分。HSC 70或LAMP 2A的过表达降低了HIF-1 α蛋白水平，而敲低则具有相反的效果。最后，缺氧增加了参与CMA和癌细胞中溶酶体生物合成的基因的转录。因此，药理学和遗传学方法鉴定CMA作为HIF-1活性的主要调节剂，并鉴定自噬和对缺氧的反应之间的相互作用。
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that mediates adaptive responses to hypoxia. We demonstrate that lysosomal degradation of the HIF-1 alpha subunit by chaperone-mediated autophagy (CMA) is a major regulator of HIF-1 activity. Pharmacological inhibitors of lysosomal degradation, such as bafilomycin and chloroquine, increased HIF-1 alpha levels and HIF-1 activity, whereas activators of chaper-one-mediated autophagy, including 6-aminonicotinamide and nutrient starvation, decreased HIF-1 alpha levels and HIF-1 activity. In contrast, macroautophagy inhibitors did not increase HIF-1 activity. Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity. HIF-1 alpha interacts with HSC70 and LAMP2A, which are core components of the CMA machinery. Overexpression of HSC70 or LAMP2A decreased HIF-1 alpha protein levels, whereas knockdown had the opposite effect. Finally, hypoxia increased the transcription of genes involved in CMA and lysosomal biogenesis in cancer cells. Thus, pharmacological and genetic approaches identify CMA as a major regulator of HIF-1 activity and identify interplay between autophagy and the response to hypoxia.