Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress
Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress
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p62/Sequestosome1 的泛素化可激活其自噬受体功能并控制泛素应激时的选择性自噬。
DOI：
10.1038/cr.2017.40
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发表时间：
2017-05-01
期刊：
影响因子：
44.1
通讯作者：
Hu, Ronggui
中科院分区：
文献类型：
--
作者：
Peng, Hong;Yang, Jiao;Hu, Ronggui
细胞泛素 (Ub) 稳态的改变（称为 Ub 应激）在多种条件下影响细胞反应，但其潜在机制尚不完全清楚。在这里，我们报道自噬受体 p62/sequestosome-1 与 E2 Ub 结合酶 UBE2D2 和 UBE2D3 相互作用。内源性 p62 在 Ub 稳态上调期间经历 E2 依赖性泛素化，这种情况称为 Ub(+) 应激，是 Ub 过度表达、热休克或化疗药物硼替佐米长期蛋白酶体抑制所固有的。 p62 的泛素化会破坏 p62 UBA 结构域的二聚化，从而释放其识别多泛素化货物以进行选择性自噬的能力。我们进一步证明，这种机制可能对于 Ub(+) 应激条件下的自噬激活至关重要。描述 p62 在感知 Ub 应激和控制选择性自噬中的机制和调节作用，有助于理解和调节细胞对各种内源性和环境挑战的反应，有可能为开发针对自噬相关疾病的治疗策略开辟新途径。
Alterations in cellular ubiquitin (Ub) homeostasis, known as Ub stress, feature and affect cellular responses in multiple conditions, yet the underlying mechanisms are incompletely understood. Here we report that autophagy receptor p62/sequestosome-1 interacts with E2 Ub conjugating enzymes, UBE2D2 and UBE2D3. Endogenous p62 undergoes E2-dependent ubiquitylation during upregulation of Ub homeostasis, a condition termed as Ub(+) stress, that is intrinsic to Ub overexpression, heat shock or prolonged proteasomal inhibition by bortezomib, a chemotherapeutic drug. Ubiquitylation of p62 disrupts dimerization of the UBA domain of p62, liberating its ability to recognize polyubiquitylated cargoes for selective autophagy. We further demonstrate that this mechanism might be critical for autophagy activation upon Ub(+) stress conditions. Delineation of the mechanism and regulatory roles of p62 in sensing Ub stress and controlling selective autophagy could help to understand and modulate cellular responses to a variety of endogenous and environmental challenges, potentially opening a new avenue for the development of therapeutic strategies against autophagy-related maladies.