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The Mpro-mediated limited proteolysis of the viral polyproteins is necessary for the replication of the virus, and cleavage of the host proteins of the infected cells may also contribute to viral pathogenesis, such as evading the immune responses or triggering cell toxicity. Therefore, the identification of host substrates of the viral protease is of special interest. To identify cleavage sites in cellular substrates of SARS-CoV-2 Mpro, we determined changes in the HEK293T cellular proteome upon expression of the Mpro using two-dimensional gel electrophoresis. The candidate cellular substrates of Mpro were identified by mass spectrometry, and then potential cleavage sites were predicted in silico using NetCorona 1.0 and 3CLP web servers. The existence of the predicted cleavage sites was investigated by in vitro cleavage reactions using recombinant protein substrates containing the candidate target sequences, followed by the determination of cleavage positions using mass spectrometry. Unknown and previously described SARS-CoV-2 Mpro cleavage sites and cellular substrates were also identified. Identification of target sequences is important to understand the specificity of the enzyme, as well as aiding the improvement and development of computational methods for cleavage site prediction.<\/jats:p>","DOI":"10.3390\/ijms24043236","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T01:56:48Z","timestamp":1675735008000},"page":"3236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Identification of SARS-CoV-2 Main Protease (Mpro) Cleavage Sites Using Two-Dimensional Electrophoresis and In Silico Cleavage Site Prediction"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5898-0166","authenticated-orcid":false,"given":"No\u00e9mi","family":"Miltner","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-8758","authenticated-orcid":false,"given":"Gerg\u0151","family":"Kall\u00f3","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4373-2175","authenticated-orcid":false,"given":"\u00c9va","family":"Cs\u0151sz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1ri\u00f3","family":"Miczi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-914X","authenticated-orcid":false,"given":"Tibor","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry, Faculty of Science and Technology, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-5996","authenticated-orcid":false,"given":"Mohamed","family":"Mahdi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6079-5621","authenticated-orcid":false,"given":"J\u00e1nos Andr\u00e1s","family":"M\u00f3ty\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5076-8729","authenticated-orcid":false,"given":"J\u00f3zsef","family":"T\u0151zs\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165878","DOI":"10.1016\/j.bbadis.2020.165878","article-title":"Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach","volume":"1866","author":"Naqvi","year":"2020","journal-title":"Biochim. 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