Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis
Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis
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DOI：
10.1016/j.freeradbiomed.2011.01.033
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发表时间：
2011-05-01
影响因子：
7.4
通讯作者：
Kruszewski, Marcin K.
中科院分区：
文献类型：
--
作者：
Stepkowski, Tomasz M.;Kruszewski, Marcin K.
氧化应激，细胞巯基水平和氧化还原平衡的扰动，影响许多细胞功能，包括信号传导途径。反过来，这可能导致诱导自噬或凋亡。NRF 2/KEAP 1信号通路是负责细胞防御氧化应激和维持细胞氧化还原平衡在生理水平的主要途径。NRF 2/KEAP 1信号传导与细胞凋亡和自噬调节之间的关系尚未完全了解。在这篇假设文章中，我们讨论了KEAP 1蛋白及其直接相互作用物（如PGAM 5，前胸腺素α，FAC 1（BPTF）和p62）如何为NRF 2/KEAP 1，细胞凋亡和自噬途径之间可能的串扰提供分子基础。我们提出了一个假设，如何NRF 2/KEAP 1可能会干扰细胞凋亡的调节机制，通过激活ASK 1激酶的KEAP 1结合伙伴-PGAM 5。基于最近的实验证据，还提出了在自噬相关的“分子枢纽”蛋白p62的背景下NF-κ B和NRF 2/KEAP 1通路之间的串扰的新假设。KEAP 1分子结合伴侣在细胞凋亡调控中的作用，在癌变和神经退行性疾病进行了讨论。(C)2011 Elsevier Inc. All rights reserved.
Oxidative stress, perturbations in the cellular thiol level and redox balance, affects many cellular functions, including signaling pathways. This, in turn, may cause the induction of autophagy or apoptosis. The NRF2/KEAP1 signaling pathway is the main pathway responsible for cell defense against oxidative stress and maintaining the cellular redox balance at physiological levels. The relation between NRF2/KEAP1 signaling and regulation of apoptosis and autophagy is not well understood. In this hypothesis article we discuss how KEAP1 protein and its direct interactants (such as PGAM5, prothymosin alpha, FAC1 (BPTF), and p62) provide a molecular foundation for a possible cross-talk between NRF2/KEAP1, apoptosis, and autophagy pathways. We present a hypothesis for how NRF2/KEAP1 may interfere with the cellular apoptosis-regulatory machinery through activation of the ASK1 kinase by a KEAP1 binding partner-PGAM5. Based on very recent experimental evidence, new hypotheses for a cross-talk between NF-kappa B and the NRF2/KEAP1 pathway in the context of autophagy-related "molecular hub" protein p62 are also presented. The roles of KEAP1 molecular binding partners in apoptosis regulation during carcinogenesis and in neurodegenerative diseases are also discussed. (C) 2011 Elsevier Inc. All rights reserved.