Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Neuroscience Research Center, GENUV Inc., Seoul 04520, Korea.
Biomolecules. 2021 May 22;11(6):779. doi: 10.3390/biom11060779.
Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin-proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14's UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome's activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential.
虽然泛素化被广泛认为是泛素蛋白酶体途径中唯一受调控的步骤，但最近的研究表明，有几种重要的机制可以调节 26S 蛋白酶体的活性。细胞中的大多数蛋白酶体都是无活性的，但在与泛素化底物结合后，通过两步机制被激活，需要泛素链与 Usp14 结合，然后与 ATP 酶松散折叠的蛋白结构域结合。最初的激活步骤由 Usp14 的 UBL 结构域发出信号，许多含有 UBL 结构域的蛋白（例如 Rad23、Parkin）也能激活蛋白酶体。ZFAND5 是一种独特的激活剂，它能结合泛素缀合物和蛋白酶体，并在肌肉萎缩过程中刺激蛋白水解。蛋白酶体的活性还可以通过亚基磷酸化来调节。提高 cAMP 并激活 PKA 的药物能在几分钟内刺激 Rpn6 磷酸化，并增强短寿命蛋白的选择性降解。同样地，提高 cAMP 的激素、禁食和运动也能激活靶组织中的蛋白酶体和蛋白水解。提高 cGMP 并激活 PKG 的药物也能刺激 26S 活性，但修饰不同的亚基，并刺激长寿命细胞蛋白的降解。这两种激酶都能增强易聚集蛋白的选择性降解，这些蛋白会导致神经退行性疾病。这些调节蛋白水解的新机制具有明显的生理重要性和治疗潜力。
