Membrane-type I matrix metalloproteinase (MT1-MMP), lipid metabolism, and therapeutic implications

Abstract

Lipids exert many essential physiological functions, such as serving as a structural component of biological membranes, storing energy, and regulating cell signal transduction. Dysregulation of lipid metabolism can lead to dyslipidemia related to various human diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, lipid metabolism is strictly regulated through multiple mechanisms at different levels, including the extracellular matrix. Membrane-type I matrix metalloproteinase (MT1-MMP), a zinc-dependent endopeptidase, proteolytically cleaves extracellular matrix components and non-matrix proteins, thereby regulating many physiological and pathophysiological processes. Emerging evidence supports the vital role of MT1-MMP in lipid metabolism. For example, MT1-MMP mediates ectodomain shedding of low-density lipoprotein receptor and increases plasma low-density lipoprotein cholesterol levels and the development of atherosclerosis. It also increases the vulnerability of atherosclerotic plaque by promoting collagen cleavage. Furthermore, it can cleave the extracellular matrix of adipocytes, affecting adipogenesis and the development of obesity. Therefore, the activity of MT1-MMP is strictly regulated by multiple mechanisms, such as autocatalytic cleavage, endocytosis and exocytosis, and posttranslational modifications. Here, we summarize the latest advances in MT1-MMP, mainly focusing on its role in lipid metabolism, the molecular mechanisms regulating the function and expression of MT1-MMP, and their pharmacotherapeutic implications.

The serum of COVID-19 asymptomatic patients up-regulates proteins related to endothelial dysfunction and viral response in circulating angiogenic cells ex-vivo

“…MMP14 promotes LDL receptors shedding (Alabi et al 2021 ), and it also participates in tissue remodeling by degrading several extracellular matrix components (collagen, gelatin, fibronectin, etc. ), which is usually associated to inflammation (Xia et al 2021 ; Hwang et al 2004 ). Overall, MMP14 may regulate the infiltration and migration of inflammatory precursor cells under arterial inflammation (Ries et al 2007 ).…”

Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor

“…Therefore, it is possible that the deletion mutant can target LDLR more effectively than the wild-type MT1-MMP because it loses the ability to bind to other substrates. The cytoplasmic tail of MT1-MMP plays an important role in endocytosis of MT1-MMP and the localization of MT1-MMP on the specific microdomains in the plasma membrane (19,(23)(24)(25). Deletion of the cytoplasmic tail did not affect the trafficking of MT1-MMP to the plasma membrane nor its ability to activate proMMP2, but the mutant proteins displayed a different distribution pattern on the cell surface and an impaired ability to mediate cell invasion compared to the wildtype protein (59,60).…”

“…It has been reported that plasma levels of sLDLR are positively correlated to circulating LDL-C levels ( 15 – 17 ). In our previous studies, we found that membrane type 1-matrix metalloproteinase (MT1-MMP) promotes ectodomain shedding of LDLR, thereby increasing plasma LDL-C levels and exacerbating the development of atherosclerosis in mice ( 18 , 19 ). Therefore, targeting MT1-MMP has the potential to be a new lipid-lowering strategy.…”

“…Structurally, MT1-MMP contains an N-terminal signal peptide, a prodomain, and then a catalytic domain with the conserved zinc-binding site (HE240XGHXXGXXH). Next is a flexible hinge region, a hemopexin (HPX) domain that links the catalytic domain, a transmembrane domain that anchors the protein to cell membranes, and a C-terminal cytoplasmic tail involved in endocytosis of MT1-MMP ( 19 , 23 – 25 ). The catalytic domain is highly conserved among MMP family members ( 19 , 24 ).…”

“…Next is a flexible hinge region, a hemopexin (HPX) domain that links the catalytic domain, a transmembrane domain that anchors the protein to cell membranes, and a C-terminal cytoplasmic tail involved in endocytosis of MT1-MMP ( 19 , 23 – 25 ). The catalytic domain is highly conserved among MMP family members ( 19 , 24 ). Clinical trials of all broad-spectrum MMP inhibitors that target the catalytic domain in oncology have failed due to lack of inhibitor specificity ( 26 ).…”