School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.
Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK.
Int J Mol Sci. 2021 May 29;22(11):5817. doi: 10.3390/ijms22115817.
Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.
胰凝乳蛋白酶样蛋白酶（TLPs）属于丝氨酸酶家族，其主要底物特异性为 P1 位的碱性残基赖氨酸和精氨酸。虽然最初被认为是在细胞外分泌的可溶性酶，但后来发现了一些新的锚定在细胞膜上的 TLPs。黏液阻塞性肺病（MucOLDs）的特征是小气道中高浓度黏液的积聚，导致持续的炎症、感染和蛋白酶活性失调。尽管中性粒细胞丝氨酸蛋白酶，特别是中性粒细胞弹性蛋白酶，与炎症的传播和局部组织破坏有关，但鉴于许多这些酶在激活上皮钠离子通道（ENaC）和蛋白酶激活受体 2（PAR2）方面发挥的作用，TLPs 也可能参与各种与疾病相关的过程。最近，人们对宿主 TLPs 激活 SARS-CoV-2 等病毒的作用给予了极大的关注。本综述的目的是强调与 ENaC 和 PAR2 激活相关的关键 TLPs，以及它们分别与气道脱水和炎症信号通路的关联。还将在抑制 TLPs 活性和这些蛋白酶作为治疗靶点的潜力的背景下讨论 TLPs 在病毒感染性方面的作用。
