The Role of ADAM17 in Inflammation-Related Atherosclerosis

Tang, Bai-Yi; Ge, Jian; Wu, Yang; Wen, Juan; Tang, Xiaohong

doi:10.1007/s12265-022-10275-4

Cited by 7 publications

(10 citation statements)

References 134 publications

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“…ADAM17 is a member of the adamalysins subfamily of metzincin metalloproteinases consisting of 824 amino acids with zinc-dependent catalytic activities (29). The human ADAM17 protein sequence contains an N-terminal signal sequence (SS), a prodomain (PD), a catalytic metalloprotease domain (MD), a disintegrin domain (DD), a membraneproximal protein domain (MPD), a conserved ADAM17 interaction sequence (CANDIS), a transmembrane domain (TM), and a C-terminal cytoplasmic domain (CD), which are located at amino acid residues 1-17, 18-216, 217-474, 480-559, 581-642, 643-666, 672-694, and 695-824, respectively (7,30) (Figure 1A). Among them, the first five protein sequences that make up its extracellular domain may be involved in regulating multiple biological functions, including angiogenesis, cell migration, cell proliferation, inflammation, and immune responses.…”

Section: Structure Of Adam17mentioning

confidence: 99%

“…In addition, the positively charged motif (Arg 625 -Lys 628 ) in MPD binds to phosphatidylserine in the outer membrane, affects the conformation of ADAM17, and induces its activation (46). TM and CD mainly regulate the response of exocytodomain signaling molecule-related events (7,38,47), which may be attributed to the functional assembly of the Src SH3-binding motif (20). The CANDIS domain lies between MPD and TM, consisting of amino acid residues 643-666 (48), which binds to the type I transmembrane protein IL-6R but not the type II transmembrane protein TNF-a (49).…”

Section: Structure Of Adam17mentioning

confidence: 99%

“…In addition to post-translational modifications, ADAM17 also affects post-transcriptional regulation. ADAM17 is highly expressed or upregulated in cancer (76,77) and other inflammation-related diseases, including kidney disease (78), sepsis (79), cicatrization (80), diabetic retinopathy (81), myocardial fibrosis (82), aortic dissection (83), arthritis (84) and atherosclerosis (7). The guanine-cytosine (G-C) sequences in the promoter region of ADAM17 are capable of binding specifically to many transcription factors (85)(86)(87).…”

Section: Adam17 Affects Post-transcriptional Regulationmentioning

confidence: 99%

“…Due to the shedding activity, ectodomains of many transmembrane proteins are hydrolyzed and released by ADAMs metalloproteinases. Studies over the past five years revealed that ADAM17 has more than 90 substrates (7,32) with distinct functions (Table 1), which are involved in various cellular processes, including cell adhesion, migration, development, inflammation, immune response, tumorigenesis, signal transduction. The cleavage and release of substrates (inflammatory cytokines, growth factors, receptors, adhesion molecules, and others) for ADAM17 may result in different functions of substrate proteins.…”

Section: Adam17 Mediates Substrate Shedding Activitymentioning

confidence: 99%

“…Activation of ADAM17 is required for the cleavage of its prodomain and exposure of the active site. In response to the inflammatory stimuli, activated ADAM17 prompts multiple receptor-mediated signal transduction by cleaving ectodomains of membrane proteins, including inflammatory cytokines, growth factors, receptors, and adhesion factors (7). The expression of ADAM17 in mouse articular cartilage is positively correlated with the development of arthritis, and its deletion attenuates articular cartilage degeneration (8).…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory role of metalloproteinase ADAM17 in tumor development

et al. 2022

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ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.

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Section: Structure Of Adam17mentioning

confidence: 99%

Section: Structure Of Adam17mentioning

confidence: 99%

Section: Adam17 Affects Post-transcriptional Regulationmentioning

confidence: 99%

Section: Adam17 Mediates Substrate Shedding Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory role of metalloproteinase ADAM17 in tumor development

et al. 2022

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Anti-inflammation nanomedicine shots through atherosclerotic plaques for targeted treatment and precise diagnosis

Zhu

Chatterjee

et al. 2023

Materials & Design

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ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice

Turkson,

Haller,

Jaeschke

et al. 2024

ATVB

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BACKGROUND: apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk. METHODS: An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow–derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)–treated macrophages was determined by Western blot analysis. RESULTS: Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet–fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow–derived cells instead of non-bone marrow–derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK–dependent manner. CONCLUSIONS: The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK–dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.

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The Role of ADAM17 in Inflammation-Related Atherosclerosis

Cited by 7 publications

References 134 publications

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Anti-inflammation nanomedicine shots through atherosclerotic plaques for targeted treatment and precise diagnosis

ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice

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