de Groot, R

Kwok, HF

Santamaria, S

Scilabra, SD

Yamamoto, K

English

UCL Discovery

Editorial: ADAM, ADAMTS andastacin proteases: Challenges andbreakthroughs in the -Omicsera-Volume IIHang Fai Kwok1, Kazuhiro Yamamoto2, Rens de Groot3,Simone Dario Scilabra4 and Salvatore Santamaria5*1Cancer Centre, Faculty of Health Sciences, MOE Frontiers Science Center for Precision Oncology,University of Macau, Avenida de Universidade, Taipa, China, 2Institute of Life Course andMedical Sciences,University of Liverpool, Liverpool, United Kingdom, 3Institute of Cardiovascular Science, UniversityCollege London, London, United Kingdom, 4Proteomics Group of Fondazione Ri.MED, Department ofResearch IRCCS ISMETT, Palermo, Italy, 5Department of Biochemical Sciences, School of Biosciences,Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomKEYWORDSADAM, ADAMTS, astacin, extracellular matrix, proteases, reprolysin family of zincmetalloproteases, M12B metalloproteasesEditorial on the Research TopicADAM, ADAMTS and astacin proteases: Challenges and breakthroughs inthe -Omics era-Volume IIADAMs (A Disintegrin and Metalloproteinases), ADAMTS (A Disintegrin andMetalloproteinase with Thrombospondin motifs) and astacins are three sub-families ofproteases belonging to the metzincin superfamily. In Volume II of ADAM, ADAMTS andAstacin Proteases: Challenges and Breakthroughs in the -Omics Era we illustrate how the-Omics Era has changed our comprehension of the biological roles of these proteases.An analysis of representative molecular structures, sequence similarity and phylogeneticorigins of astacins performed by Gomis-Rüth and Stöcker identified the potential origin ofastacins in unicellular holozoans, the precursor of metazoans (multicellular organisms).They suggest that the scattered presence of astacins across the different kingdoms of life mayhave occurred due to horizontal gene transfer from holozoans.Meprin β is a type I transmembrane astacin the expression of which is associated withcertain types of cancer, including melanoma. Volume I of this Research Topic showed theimpact of meprin β variants on the invasiveness of tumor cells (Gellrich et al., 2021). In thisVolume II, Wöhner et al. identified meprin β as a protease responsible for ectodomainshedding of CD44, a transmembrane glycoprotein expressed in several different tumors.Proteolytic processing of the CD44 ectodomain leads to release of intracellular fragments,which triggers transcriptional modifications. The authors found a unique regulatory loop atthe transcriptional level for CD44, matrix metalloproteinase 2 (MMP2) and CD44 sheddasesincluding MMP14 and ADAM10, which may contribute to the development of cancer.ADAM17 is another metzincin that has attracted considerable interest due to itsinvolvement in inflammation and cancer (Moss and Minond, 2017). A novel bi-specificinhibitor was developed by Weizman et al. that simultaneously targets ADAM17 and theproinflammatory cytokine TL1A. They propose it has high therapeutic potential in theOPEN ACCESSEDITED AND REVIEWED BYAndrea Mozzarelli,University of Parma, Italy*CORRESPONDENCESalvatore Santamaria,s.santamaria@surrey.ac.ukSPECIALTY SECTIONThis article was submitted to ProteinBiochemistry for Basic and AppliedSciences, a section of the journalFrontiers in Molecular BiosciencesRECEIVED 23 February 2023ACCEPTED 23 February 2023PUBLISHED 07 April 2023CITATIONKwok HF, Yamamoto K, de Groot R,Scilabra SD and Santamaria S (2023),Editorial: ADAM, ADAMTS and astacinproteases: Challenges and breakthroughsin the -Omics era-Volume II.Front. Mol. Biosci. 10:1172288.doi: 10.3389/fmolb.2023.1172288COPYRIGHT© 2023 Kwok, Yamamoto, de Groot,Scilabra and Santamaria. This is an open-access article distributed under the termsof the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums ispermitted, provided the original author(s)and the copyright owner(s) are creditedand that the original publication in thisjournal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.Frontiers in Molecular Biosciences frontiersin.org01TYPE EditorialPUBLISHED 07 April 2023DOI 10.3389/fmolb.2023.1172288treatment of inflammatory bowel disease. When fused together, thetwo inhibitory domains displayed a synergistic effect thatdramatically increased the potency of this novel therapeutic option.The ADAMTS sub-family of metzincins comprises 19 secretedmembers in humans, with roles ranging from cleavage of extracellularmatrix (ECM) proteins to platelet aggregation (Dubail and Apte, 2015).ADAMTS5 is best known for its role in osteoarthritis, where it drivescartilage degradation by cleaving the proteoglycan aggrecan(Santamaria, 2020). A single nucleotide polymorphism in ADAMTS5has been associated with severe lumbar disc degeneration (Rajasekaranet al., 2015) and Adamts5 deletion protected from intervertebral discdegeneration (IDD) in a mouse model of the disease (Ngo et al., 2017).Jing and Liu describe an interplay between long nuclear RNAs(lncRNAs) and microRNAs (miRNAs) in the regulation ofADAMTS5 expression in ID-derived nucleus pulpous cells. ThelncRNA HOXC13-antisense (AS) induced a catabolic responsecharacterized by increased expression of ADAMTS5 as well asMMP3, ADAMTS4 and a number of pro-inflammatory cytokines,while down-regulating expression of anabolic markers such asaggrecan and collagen type II. This action of lncRNA HOXC13-ASwas directly antagonized by miR-497-5p, which down-regulatedADAMTS5 expression and whose expression levels negativelycorrelated with IDD severity in patients. Since HOXC13-AS down-regulated miR-497-5p expression, this lncRNA may represent a masterregulator of ADAMTS5 in intervertebral discs. Although othermicroRNAs have been involved in ADAMTS5 regulation such asmiR-137 (Zhang et al., 2019) and miR-145 (Hu et al., 2017),expression of ADAMTS5 is also regulated at the post-translationallevel (Santamaria, 2020), therefore dysregulatedADAMTS5 activitymaybe a product of multiple converging regulatory mechanisms.Null mutations in ADAMTS10 are associated with a recessive formof Weill-Marchesani syndrome, characterized by eye abnormalities(Dagoneau et al., 2004). Mutations in fibrillin-1 (FBN1) lead to adominant, albeit clinically indistinguishable, form of the syndrome(Faivre et al., 2003), indicating overlapping functions of the twoproteins. Fibrillin1 microfibrils can function as reservoirs of latenttransforming growth factor beta (TGFβ), thereby controlling TGFβavailability and function.Wareham et al. used zebrafish (Danio rerio) asan in vivo model to investigate the link between ADAMTS10 andfibrillin1 in ocular development. They found that ADAMTS10 isrequired to cleave fibrillin1 microfibrils and liberate TGFβ. In turn,activation of the TGFβ pathway is necessary for the development of theoptic nerve. Altogether, the study reported a novel function ofADAMTS10 in the development of retinal ganglion cells, that ismediated by its ability to liberate TGFβ from fibrillin1 microfibrilsand initiate TGFβ signaling.The link between TGFβ pathway, fibrillin microfibrils andADAMTSs is further explored in the review paper by Mead onADAMTS6, a protease involved in musculoskeletal andcardiovascular development (Santamaria and de Groot, 2020).Deletion of Adamts6 in mice is embryonically lethal due to variouscongenital heart defects (Prins et al., 2018). Previous work byMead et al.(2022) has shown that the knockout embryos also present withappendicular skeletal abnormalities as well as axial skeletonmanifestations and facial deformities. The molecular mechanismsare still being elucidated but ADAMTS6 binding to and cleavage ofboth fibrillins and latent TGFβ binding proteins (LTBPs) point to a rolein TGFβ signaling (Cain et al., 2022; Mead et al., 2022). Indeed, a recentstudy by Cain et al. (2022) showed that ADAMTS6 can cleaveLTBP3 and overexpression of ADAMTS6 increased TGFβ activationin a dose dependent manner, following stimulation with matureTGFβ1. ADAMTS6 was first identified to be expressed in humanplacental tissue (Hurskainen et al., 1999) and the Human Protein Atlasreports that in humans ADAMTS6 is expressed in the placenta andendometrium at both RNA and protein levels (https://www.proteinatlas.org/ENSG00000049192-ADAMTS6/tissue). The CancerGenome Atlas also shows that both ADAMTS6 and fibrillin3 areexpressed in endometrial cancer, the latter being an unfavorableprognostic marker. Wächter et al. (2022) found co-expression ofADAMTS6 and fibrillin-2 in cytotrophoblasts and, in the ClinVardatabase, an ADAMTS6 mutation in a patient with primary ovarianinsufficiency has been reported as likely pathogenic. Together, thesedata suggest a role of ADAMTS6 in pregnancy and possibly inendometrial cancer, which also needs to be further explored.In summary, this Volume II elucidates novel roles of ADAMs,ADAMTSs and astacins in development, inflammatory anddegenerative conditions and cancer. It also offers innovativeapproaches to target dysregulated metzincin activities at differentlevels of regulation. The picture that emerges from these studies isone characterized by many interconnections between ECM proteinsand exquisite fine tuning of proteolytic activity. As highlighted inthis Research Topic, tackling such a daunting complexity requires amultidisciplinary as well as mechanistic approach.Author contributionsHFK, KY, RdG, SDS, and SS planned, wrote, and revised theeditorial manuscript. All authors contributed to the article andapproved the submitted version.FundingThe work of the authors is supported by funds from the VersusArthritis (21447 to KY), the Fondazione con il Sud within the “Brains toSouth“ program (Grant Agreement No. 2018–PDR–00799 to SDS), theScience and Technology Development Fund of Macau SAR (FDCT)(0010/2021/AFJ and 0027/2022/A1 to HFK) and the British HeartFoundation (FS/IBSRF/20/25032 to SS).Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authors anddo not necessarily represent those of their affiliated organizations, orthose of the publisher, the editors and the reviewers. Any product thatmay be evaluated in this article, or claim that may be made by itsmanufacturer, is not guaranteed or endorsed by the publisher.Frontiers in Molecular Biosciences frontiersin.org02Kwok et al. 10.3389/fmolb.2023.1172288ReferencesCain, S. A., Woods, S., Singh, M., Kimber, S. J., and Baldock, C. (2022).ADAMTS6 cleaves the large latent TGFβ complex and increases the mechanotensionof cells to activate TGFβ. Matrix Biol. 114, 18–34. doi:10.1016/j.matbio.2022.11.001Dagoneau, N., Benoist-Lasselin, C., Huber, C., Faivre, L., Mégarbané, A., Alswaid, A.,et al. (2004). ADAMTS10 mutations in autosomal recessive Weill Marchesanisyndrome. Am. J. Hum. Genet. 75 (5), 801–806. doi:10.1086/425231Dubail, J., and Apte, S. S. (2015). Insights on ADAMTS proteases and ADAMTS-likeproteins from mammalian genetics. Matrix Biol. 44-46, 24–37. doi:10.1016/j.matbio.2015.03.001Faivre, L., Gorlin, R. J., Wirtz, M. K., Godfrey, M., Dagoneau, N., Samples, J. R., et al.(2003) In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesanisyndrome. J. Med. Genet. 40(1):34–36. doi:10.1136/jmg.40.1.34Gellrich, A., Scharfenberg, F., Peters, F., Sammel, M., Helm, O., Armbrust, F., et al.(2021). Characterization of the cancer-associated meprin ßeta variants G45R and G89R.Front. Mol. Biosci. 8, 702341. doi:10.3389/fmolb.2021.702341Hu, G., Zhao, X., Wang, C., Geng, Y., Zhao, J., Xu, J., et al. (2017). MicroRNA-145attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via directsuppression of MKK4. Cell Death Dis. 8 (10), e3140. doi:10.1038/cddis.2017.522Hurskainen, T. L., Hirohata, S., Seldin, M. F., and Apte, S. S. (1999). ADAM-TS5,ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases.General features and genomic distribution of the ADAM-TS family. J. Biol. Chem. 274(36), 25555–25563. doi:10.1074/jbc.274.36.25555Mead, T. J., Martin, D. R., Wang, L. W., Cain, S. A., Gulec, C., Cahill, E., et al. 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Genetic susceptibility of lumbar degenerative disc disease in youngIndian adults. Eur. Spine J. 24 (9), 1969–1975. doi:10.1007/s00586-014-3687-ySantamaria, S., and de Groot, R. (2020). ADAMTS proteases in cardiovascularphysiology and disease. Open Biol. 10 (12), 200333. doi:10.1098/rsob.200333Santamaria, S. (2020). ADAMTS-5: A difficult teenager turning 20. Int. J. Exp. Pathol.101 (1-2), 4–20. doi:10.1111/iep.12344Wächter, J., Shannon, M. J., and Beristain, A. G. (2022). Transcriptomic mapping ofthe metzincin landscape in human trophoblasts. Gene Expr. Patterns 46, 119283. doi:10.1016/j.gep.2022.119283Zhang, Y., Wang, G., Ma, L., Wang, C., Wang, L., Guo, Y., et al. (2019) miR-137suppresses cell growth and extracellular matrixdegradation through regulatingADAMTS-5 in chondrocytes. Am. J. Transl. Res. 11(11):7027–7034. PMID:31814906; PMCID: PMC6895521.Frontiers in Molecular Biosciences frontiersin.org03Kwok et al. 10.3389/fmolb.2023.1172288

Editorial: ADAM, ADAMTS and astacin proteases: Challenges and breakthroughs in the -Omics era-Volume II

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Editorial: ADAM, ADAMTS and astacin proteases: Challenges and breakthroughs in the -Omics era-Volume II

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