Department of Veterinary Sciences, University of Turin, Largo P. Braccini 2, 10095 Grugliasco, Italy.
Biomolecules. 2021 Feb 5;11(2):228. doi: 10.3390/biom11020228.
PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog.
PA28（也称为 11S、REG 或 PSME）是一种蛋白酶体调节因子家族，其成员广泛存在于许多真核超类群中。在有颚脊椎动物中，它们由三个同源物 PA28α、PA28β 和 PA28γ 组成，这些同源物组装成七聚体异源（PA28αβ）或同源（PA28γ）环，位于 20S 蛋白酶体圆柱形结构的一个或两个末端。虽然它们具有高度的序列和结构相似性，但这三种同工型在生化和生物学特性方面有很大的不同。事实上，PA28α 和 PA28β 似乎出现得更晚，进化得更快，以执行专门针对 MHC I 类抗原呈递过程的新功能。与之相符的是，PA28αβ 有利于蛋白酶体释放肽产物，特别适合支持适应性免疫反应，而不影响蛋白质底物的水解速率。相反，PA28γ 似乎是一个进化缓慢的基因，与 PA28 激活剂家族的共同祖先最为相似，很可能保留了其原始功能。值得注意的是，PA28γ 主要定位于核内，参与调节包括细胞生长和增殖、细胞凋亡、染色质结构和组织以及对 DNA 损伤的反应等多种重要的细胞过程。与 PA28αβ 的活性形成鲜明对比的是，PA28γ 的大多数这些不同的生物学功能似乎依赖于其明显增强 20S 蛋白酶体对调节蛋白降解速率的能力。本综述将重点介绍 PA28γ 的分子机制和生化特性，这些特性可能解释了其复杂多样的生物学功能，并突出了与 PA28αβ 同源物的共同特征。
