E3泛素连接酶Pellino蛋白的研究进展
徐 艳,赵保兵*

(山东大学药学院,新药药理研究所,山东 济南 250012)

Pellino蛋白; 泛素连接酶; 炎症; 免疫; 癌症

Research progress on E3 ubiquitin ligase Pellino proteins
XU Yan,ZHAO Baobing*

(School of Pharmaceutical Sciences,Institute of New Drug Pharmacology,Shandong University,Jinan 250012,China)

Pellino protein; ubiquitin ligase; inflammation; immunity; cancer

DOI: 10.6043/j.issn.0438-0479.202111010

备注

Pellino蛋白是近年来新发现的一类E3泛素连接酶,通过靶蛋白泛素化介导蛋白降解、蛋白与蛋白的相互作用、蛋白质细胞定位以及信号传导.目前研究表明Pellino蛋白在固有免疫细胞和获得性免疫细胞中具有重要调控作用,与炎症和自身免疫密切相关.本文总结了近年来Pellino蛋白的表达与活性调控、介导的信号转导途径以及在免疫细胞中的分子调控机制的研究成果,同时探讨了Pellino蛋白在自身免疫、炎症、癌症、心脏疾病及肥胖疾病中的作用,并结合目前的研究进展提出新的科学问题和发展方向.

Background: Ubiquitination is a post-translational modification of proteins in both normal homeostasis and disease. This process involves the addition of an evolutionarily conserved small protein, ubiquitin (Ub) or ubiquitin-like proteins (UBLs), which is mediated by a cascade of enzymatic reactions carried out by activating (E1), conjugating (E2) and ligating (E3) enzymes. The E3s are the critical components of this cascade owing to their strict control of both the efficiency and substrate specificity of the ubiquitination reaction. The human genome contains around 50 genes encoding E2 enzymes and 600 genes encoding E3 ligases. In addition, there are more than 90 deubiquitinating enzymes (DUBs) that can remove Ub from the Ub-bound proteins. Ubiquitination regulates a wide spectrum of cellular processes, including protein degradation, protein–protein interactions, endocytosis, cell cycle progression, and substrate activation or inactivation. The physiological functions of ubiquitination are not limited to proteolysis. There are also nonproteolytic roles of ubiquitination such as multi-protein complex assembly. Therefore, deregulation of ubiquitination can lead to several disorders due to functional mutation or aberrant expression of the Ub system components, including cancer, neurodegenerative disorders, and adaptive and innate immunity–related disorders.
Progress: Pellino proteins, a new type of E3 ubiquitin ligases, was initially identified in Drosophila as a binding partner of Pelle (the Drosophila homologue of interleukin-1 receptor-associated kinase proteins). In mammals, Pellino proteins constitute a family of four E3 ubiquitin ligases: Pellino-1, Pellino-2, and two isoforms of Pellino-3 (Pellino-3a and -3b). These Pellino proteins are highly similar in their primary structure, with each protein possessing a C-terminal RING-like domain that confers E3 ubiquitin ligase activity and a phospho-threonine-binding forkhead-associated (FHA) domain that facilitates its interaction with substrate proteins. This review discusses the regulation of Pellinos expression and activity. Phosphorylation is essential for the E3 ubiquitin ligase activity of Pellino proteins, accompanied by its auto-ubiquitination. Pellino proteins are also subject to sumoylation with unknown functions. Pellino proteins have recently been demonstrated to play important roles in the inflammation and autoimmunity by regulating protein degradation, protein-protein interactions, protein translocation and by signaling transduction through ubiquitination. The molecular roles of Pellino proteins in immune signaling are described in detail with particular emphasis on their involvement in Toll-like receptor (TLR)-dependent NF-κB signaling and MAPK signaling, TNF signaling and NOD signaling. Furthermore, the growing appreciation of the importance of Pellino proteins in a wide range of diseases is also evaluated, including autoimmunity, inflammation, cancer, heart disease and obesity.
Perspective: As our understanding of the biological functions of Pellino family increases, it is becoming clear that Pellino proteins may play important roles in other cellular events in addition to inflammation and autoimmunity. Protein structures and post-translational modifications are highly conserved across the Pellino family, suggesting that different Pellino proteins are likely regulated by similar mechanisms. However, recent findings highlight that there is functional specificity for the various members of the Pellino family. Some of the specificity may be due to cell restricted expression of individual members. Identification of an increasing number of Pellino interactors will help reveal the diverse functions of these family members. Furthermore, a detailed understanding of the basis to their functional diversity would be of immense importance to define their physiological roles. Given their dysregulated expression and regulator roles in a wide range of pathological states, Pellino proteins may consequently represent valuable targets in relevant diseases. Enhanced understanding of the mechanisms that underlie their expression, activation and substrate recognition may provide important clues for the development of new therapeutic strategies. Therefore, expanding investigation on the molecular, physiological and pathophysiological roles of the Pellino family is required for its future exploitation as therapeutic target.