The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.
The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.
复制标题
KEAP 1-NRF 2途径调节TFEB/TFE 3依赖性溶酶体生物发生。
DOI：
10.1073/pnas.2217425120
复制
发表时间：
2023-05-30
影响因子：
11.1
通讯作者：
Cox, Andrew G.
中科院分区：
文献类型：
--
作者：
Ong, Athena Jessica S.;Bladen, Cerys E.;Tigani, Tara A.;Karamalakis, Anthony P.;Evason, Kimberley J.;Brown, Kristin K.;Cox, Andrew G.
KEAP 1-NRF 2通路在氧化还原平衡和细胞代谢的调节中起着核心作用。尽管NRF 2在包括癌症在内的各种疾病状态中已被广泛研究，但关于NRF 2在胚胎发育过程中的作用的知识仍然很少。在这里，我们证明，NRF 2激活诱导的致死性之前，肝脏异常和溶酶体的积累。此外，我们发现NRF 2激活溶酶体生物发生的主调节因子TFEB/TFE 3。这些研究强调了在胚胎发育期间维持溶酶体稳态的关键作用，更广泛地说，表明异常溶酶体生物发生可能是NRF 2驱动的病理学的标志。氧化还原和代谢稳态的维持是胚胎发育不可或缺的一部分。核因子红细胞2相关因子2（NRF 2）是一种应激诱导的转录因子，在氧化还原平衡和细胞代谢的调节中发挥核心作用。在稳态条件下，NRF 2被Kelch样ECH相关蛋白1（KEAP 1）抑制。在这里，我们证明，Keap 1缺陷诱导Nrf 2激活和发育后致死。丧失活力之前会出现以溶酶体蓄积为特征的严重肝脏异常。从机制上讲，我们证明了Keap 1的缺失促进了转录因子EB（TFEB）/转录因子结合IGHM增强子3（TFE 3）依赖性溶酶体生物合成的异常激活。重要的是，我们发现NRF 2依赖的调节溶酶体生物发生是细胞自主的和进化保守的。这些研究确定了KEAP 1-NRF 2途径在调节溶酶体生物发生中的作用，并表明在胚胎发育期间需要维持溶酶体稳态。
The KEAP1–NRF2 pathway plays a central role in the regulation of redox balance and cellular metabolism. Although NRF2 has been extensively investigated in various disease states, including cancer, there is a paucity of knowledge regarding the role of NRF2 during embryonic development. Here, we demonstrate that NRF2 activation induces lethality that is preceded by liver abnormalities and accumulation of lysosomes. Moreover, we find that NRF2 activates the master regulators of lysosomal biogenesis, TFEB/TFE3. These studies highlight a critical role for the maintenance of lysosomal homeostasis during embryonic development and, more broadly, suggest that aberrant lysosomal biogenesis may be a hallmark of NRF2-driven pathologies. The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1–NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.
登录
查看更多内容
影响因子：
14.9
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
通讯作者：
Biswal S
影响因子：
64.5
作者：
Lignitto, Luca;LeBoeuf, Sarah E.;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
16.8
作者：
Dohi, Yoshihiro;Ikura, Tsuyoshi;Igarashi, Kazuhiko
通讯作者：
Igarashi, Kazuhiko
影响因子：
7.3
作者：
Martina JA;Diab HI;Lishu L;Jeong-A L;Patange S;Raben N;Puertollano R
通讯作者：
Puertollano R
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki