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Latency proteins of the virus contribute to lymphomagenesis by activating the transcription factor NF-\u03baB, however, the molecular mechanism underlying EBV-driven NF-\u03baB activation remains incompletely understood. Here we show that EBV latent membrane proteins LMP1 and LMP2A or LMP2B synergize to activate the protease MALT1, a key driver of NF-\u03baB-mediated lymphocyte proliferation. EBV-positive B-cell lines co-expressing LMP1 and LMP2 proteins exhibited constitutive MALT1 activity, and treatment with a MALT1 inhibitor or silencing of latent membrane protein-1 (LMP1) or LMP2 impaired MALT1-dependent substrate cleavage. LMP1 physically interacted with the MALT1-binding partner BCL10, while LMP2A and LMP2B interacted with MALT1. LMP1 also colocalized with LMP2 in dotted structures, suggesting that LMP1 and LMP2 synergize via the coordinated formation of LMP-BCL10-MALT1 (LBM) complexes. Finally, MALT1 protease inhibition led to reduced expression of a set of NF-\u03baB-driven genes, and reduced tumor growth in an EBV-positive lymphoma xenograft model. These findings establish a key role for the protease MALT1 in LMP1\/2-mediated, NF-\u03baB-driven cellular transformation and provide a rationale for inhibiting MALT1 to treat EBV-positive B-cell lymphomas that co-express LMP1 and LMP2.<\/jats:p>","DOI":"10.1038\/s41375-026-03109-8","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:00:02Z","timestamp":1786611602000},"page":"2455-2465","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A role for the protease MALT1 in EBV-mediated B-cell transformation by Latent Membrane Proteins 1 and 2"],"prefix":"10.1038","volume":"40","author":[{"given":"M\u00e9lanie","family":"Juilland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3871-7124","authenticated-orcid":false,"given":"Laurence","family":"Romy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harun-Or","family":"Rashid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-7408","authenticated-orcid":false,"given":"Sara Escudeiro","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0704-5506","authenticated-orcid":false,"given":"Silvia","family":"Podavini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0703-6762","authenticated-orcid":false,"given":"David","family":"Vallois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manhui","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Pandeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Fr\u00eate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"D\u00e9caillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-516X","authenticated-orcid":false,"given":"Laurence","family":"de Leval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Rothenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5656-2139","authenticated-orcid":false,"given":"Margot","family":"Thome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"3109_CR1","doi-asserted-by":"publisher","first-page":"3652","DOI":"10.1016\/j.cell.2022.08.026","volume":"185","author":"B Damania","year":"2022","unstructured":"Damania B, Kenney SC, Raab-Traub N. 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