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Although multiple downstream signaling pathways have been found to be involved in this response in a syndecan-4-dependent manner, there are likely more signaling components involved. As part of a larger syndecan-4 interactome screening, we have previously identified MLP as a binding partner to the cytoplasmic tail of syndecan-4. Interestingly, many human MLP mutations have been found in patients with hypertrophic (HCM) and dilated cardiomyopathy (DCM). To gain deeper insight into the role of the syndecan-4\u2013MLP interaction and its potential involvement in MLP-associated cardiomyopathy, we have here investigated the syndecan-4\u2013MLP interaction in primary adult rat cardiomyocytes and the H9c2 cell line. The binding of syndecan-4 and MLP was analyzed in total lysates and subcellular fractions of primary adult rat cardiomyocytes, and baseline and differentiated H9c2 cells by immunoprecipitation. MLP and syndecan-4 localization were determined by confocal microscopy, and MLP oligomerization was determined by immunoblotting under native conditions. Syndecan-4\u2013MLP binding, as well as MLP self-association, were also analyzed by ELISA and peptide arrays. Our results showed that MLP-WT and syndecan-4 co-localized in many subcellular compartments; however, their binding was only detected in nuclear-enriched fractions of isolated adult cardiomyocytes. In vitro, syndecan-4 bound to MLP at three sites, and this binding was reduced in some HCM-associated MLP mutations. While MLP and syndecan-4 also co-localized in many subcellular fractions of H9c2 cells, these proteins did not bind at baseline or after differentiation into cardiomyocyte-resembling cells. Independently of syndecan-4, mutated MLP proteins had an altered subcellular localization in H9c2 cells, compared to MLP-WT. The DCM- and HCM-associated MLP mutations, W4R, L44P, C58G, R64C, Y66C, K69R, G72R, and Q91L, affected the oligomerization of MLP with an increase in monomeric at the expense of trimeric and tetrameric recombinant MLP protein. Lastly, two crucial sites for MLP self-association were identified, which were reduced in most MLP mutations. Our data indicate that the syndecan-4\u2013MLP interaction was present in nuclear-enriched fractions of isolated adult cardiomyocytes and that this interaction was disrupted by some HCM-associated MLP mutations. MLP mutations were also linked to changes in MLP oligomerization and self-association, which may be essential for its interaction with syndecan-4 and a critical molecular mechanism of MLP-associated cardiomyopathy.<\/jats:p>","DOI":"10.3390\/cells13110947","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T12:19:46Z","timestamp":1717417186000},"page":"947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring Syndecan-4 and MLP and Their Interaction in Primary Cardiomyocytes and H9c2 Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9729-2127","authenticated-orcid":false,"given":"Thea Parsberg","family":"St\u00f8le","sequence":"first","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Lunde","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway"},{"name":"K.G. Jebsen Center for Cardiac Research, University of Oslo, 0313 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4019-1844","authenticated-orcid":false,"given":"Katja","family":"Gehmlich","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"},{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir","family":"Christensen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway"},{"name":"K.G. Jebsen Center for Cardiac Research, University of Oslo, 0313 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-6112","authenticated-orcid":false,"given":"William E.","family":"Louch","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway"},{"name":"K.G. Jebsen Center for Cardiac Research, University of Oslo, 0313 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine Rein","family":"Carlson","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","first-page":"3799","article-title":"Syndecan-4 signaling at a glance","volume":"126","author":"Elfenbein","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Finsen, A.V., Lunde, I.G., Sjaastad, I., \u00d8stli, E.K., Lyngra, M., Jarstadmarken, H.O., Hasic, A., Nyg\u00e5rd, S., Wilcox-Adelman, S.A., and Goetinck, P.F. (2011). 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