Molecular Pharmacology Group, Wolfson Link and Davidson Buildings, Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotand, UK.
Autophagy. 2010 Nov;6(8):1198-200. doi: 10.4161/auto.6.8.13479. Epub 2010 Nov 16.
Cells employ macroautophagy to deliver aggregates of misfolded and/or ubiquitinated proteins for lysosomal degradation or supply of essential macromolecules under conditions of nutrient deprivation. The former seems complementary to the proteasome system, which is likely to degrade only soluble proteins. While bulk degradation via the autophagy pathway during starvation is rather nonspecific, the recognition of proteins that are either misfolded or adopt a particular conformation and/or become ubiquitinated, requires some form of specificity. This is brought about, at least in part, by the scaffold and ubiquitin-binding protein, p62 (SQSTM1). p62 is a multidomain scaffold that sequesters other proteins and polymerizes through its Phox and Bem1p domains and binds K63-ubiquitinated proteins through its UBA domain. p62 interaction with LC3 appears critical for membrane encapsulation seen in autophagosomes. However, there is a growing body of evidence indicating that p62 is not exclusively involved in autophagy regulation, and that there are nonmembrane encapsulated, soluble subpopulations of p62 in cells. The role of these subpopulations has yet to be resolved, although one function appears to be to regulate signaling, as indicated through p62's ability to regulate NFκB activation. Signaling through the ubiquitous cyclic AMP (cAMP) system is compartmentalized, with tethered subpopulations of cAMP-degrading phosphodiesterases sculpting cAMP gradients around specific signaling complexes so as to regulate them at a spatial level. We have recently demonstrated that p62 colocalizes with a specific conformer of the cAMP degrading phosphodiesterase, PDE4A4, so as to form reversible, membrane-free cytosolic aggregates lacking LC3. This results in PDE4A4 becoming sequestered away from signaling proteins that normally sequester it, providing a means of reprogramming compartmentalized cAMP signaling in cells.
细胞利用巨自噬将错误折叠和/或泛素化的蛋白质聚集物递送至溶酶体进行降解，或者在营养缺乏的情况下提供必需的大分子物质。前者似乎与蛋白酶体系统互补，后者可能只降解可溶性蛋白质。虽然在饥饿期间通过自噬途径进行大量降解是相当非特异性的，但识别那些错误折叠或采用特定构象和/或被泛素化的蛋白质需要某种形式的特异性。这至少部分是由支架和泛素结合蛋白 p62（SQSTM1）带来的。p62 是一种多结构域支架，通过其 Phox 和 Bem1p 结构域隔离其他蛋白质并聚合，并通过其 UBA 结构域结合 K63-泛素化的蛋白质。p62 与 LC3 的相互作用对于自噬体中观察到的膜包裹至关重要。然而，越来越多的证据表明，p62 不仅仅参与自噬调节，而且细胞中还存在非膜包裹的可溶性 p62 亚群。这些亚群的作用尚未得到解决，尽管有一个功能似乎是调节信号转导，如 p62 调节 NFκB 激活的能力所表明的那样。普遍存在的环腺苷酸 (cAMP) 系统的信号转导是分隔的，带有 cAMP 降解磷酸二酯酶的固定亚群在特定信号复合物周围塑造 cAMP 梯度，以在空间水平上调节它们。我们最近证明，p62 与降解 cAMP 的磷酸二酯酶 PDE4A4 的特定构象共定位，从而形成可逆的、无膜的细胞质聚集物，缺乏 LC3。这导致 PDE4A4 被隔离远离通常隔离它的信号蛋白，为细胞中分隔的 cAMP 信号重新编程提供了一种手段。
