Membrane-anchored serine proteases in health and disease

Abstract

Serine proteases of the trypsin-like family have long been recognized to be critical effectors of biological processes as diverse as digestion, blood coagulation, fibrinolysis, and immunity. In recent years, a subgroup of these enzymes has been identified that are anchored directly to plasma membranes, either by a carboxy-terminal transmembrane domain (Type I), an amino-terminal transmembrane domain with a cytoplasmic extension (Type II or TTSP), or through a glycosylphosphatidylinositol (GPI) linkage. Recent biochemical, cellular, and in vivo analyses have now established that membrane-anchored serine proteases are key pericellular contributors to processes vital for development and the maintenance of homeostasis. This chapter reviews our current knowledge of the biological and physiological functions of these proteases, their molecular substrates, and their contributions to disease.

Fig. 1

Domain structures of the human membrane-anchored serine proteases. Structures are grouped according to similarity in domain structure to each other. Consensus domains are as indicated at the bottom of the figure. The location of each protein domain (amino acid numbering) is indicated above the domain. Amino and carboxy termini are as indicated. Protease domain: serine protease domain; activation domain: pro-domain; TM: transmembrane domain; GPI anchor: glycosylphosphatidylinositol linkage domain; LDLRA: LDL receptor class A domain; MAM: meprin, A5 antigen, and receptor protein phosphatase μ domain; CUB: Cls/Clr, urchin embryonic growth factor and bone morphogenetic protein-1; SEA: sea urchin sperm protein, enteropeptidase, agrin domain; Fz: frizzled domain; SR: Group A scavenger receptor domain.

Fig. 2

Matriptase is critical for the development and functions of the epidermis. Matriptase activation, triggered by unknown mechanisms in skin, activates the GPI-anchored prostasin zymogen. Prostasin activation is required for epidermal tight junction formation, epidermal lipid synthesis, and induction of caspase-14-calpain I, and bleomysin hydrolase-mediated processing of the epidermal polyprotein, profilaggrin, into filaggrin monomer units, and subsequently, into free hygroscopic amino acids, which participate in the formation of the cornified envelope and contribute to skin hydration. Matriptase deficiency is linked to a rare form of skin disease, referred to as autosomal recessive ichthyosis with hypotrichosis (ARIH), or ichthyosis, follicular atrophoderma, and hypotrichosis (IFAH). Matriptase is also capable of activating proinflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment and are responsible for the runaway kallikrein proteolytic cascade associated with LEKTI-deficiency/Netherton syndrome. HAI-1 regulates matriptase in the epidermis.

Fig. 3

Corin-mediated pro-ANP processing in the heart. In cardiomyocytes, ANP is made as a precursor, pro-ANP. Upon secretion, pro-ANP is cleaved by corin, generating an inactive N-terminal (NT) peptide and an active ANP. ANP promotes natriuresis, diuresis, and vasodilation, thereby reducing blood volume/pressure and improving cardiac function.