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The surface expression of MHCIIs in these cells is regulated via the ubiquitination of a single conserved lysine residue in the cytoplasmic tail of all known \u03b2-chains. This modification is carried out mainly by the MARCH1 E3 ubiquitin ligase. In MARCH1-deficient DCs, the lack of MHCII ubiquitination results in its excessive accumulation at the plasma membrane, disorganizing lipid rafts and tetraspanin webs. These membrane structures regulate numerous biological processes, allowing the interactions between signaling molecules, such as the B-cell receptor (BCR) and CD19. Nevertheless, the full impact of MARCH1 and the ubiquitin-dependent MHCII turnover on the development, activation, and functions of B cells remains to be explored. Here, we show that the absence of MHCII ubiquitination negatively affected the marginal zone (MZ) B-cell pool in mice. We provide evidence that this alteration of B-cell responses may, at least in part, be due to the proteotoxicity of MHCIIs on the CD81-containing tetraspanin web, which impacted the surface dynamics of CD19 and its capacity to activate the PI3K\/Akt cascade during tonic BCR signaling. The reduced MZ B-cell pool impaired the immune response to a type 2\u2009T-independent antigen. Interestingly, the germinal center (GC) response against a T-dependent antigen was also negatively affected. Altogether, our results demonstrate the importance of the ubiquitin-dependent control of MHCII proteostasis for B-cell functions.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf273","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T19:46:03Z","timestamp":1762890363000},"source":"Crossref","is-referenced-by-count":1,"title":["Ubiquitination of MHC class II molecules regulates B-cell development and response to antigens in mice"],"prefix":"10.1093","volume":"215","author":[{"given":"Maxime","family":"Raymond","sequence":"first","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Laboratoire d\u2019immunologie mol\u00e9culaire, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut Courtois d\u2019innovation biom\u00e9dicale, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renaud","family":"Balthazard","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Laboratoire d\u2019immunologie mol\u00e9culaire, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut Courtois d\u2019innovation biom\u00e9dicale, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Zahn","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de recherche en biologie mol\u00e9culaire des cellules B, Institut de recherches cliniques de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasha","family":"Silva-Barrios","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut national de la recherche scientifique , Laval, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akil","family":"Hammami","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut national de la recherche scientifique , Laval, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelilah","family":"Majdoubi","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Laboratoire d\u2019immunologie mol\u00e9culaire, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut Courtois d\u2019innovation biom\u00e9dicale, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun Seong","family":"Lee","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Laboratoire d\u2019immunologie mol\u00e9culaire, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut Courtois d\u2019innovation biom\u00e9dicale, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Connolly","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , 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Ontario,","place":["Canada"]},{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Solna,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c9tienne","family":"Gagnon","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut de recherche en immunologie et canc\u00e9rologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-0321","authenticated-orcid":false,"given":"Javier Marcelo","family":"Di Noia","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de recherche en biologie mol\u00e9culaire des cellules B, Institut de recherches cliniques de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"D\u00e9partement de m\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"St\u00e4ger","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut national de la recherche scientifique , Laval, Qu\u00e9bec,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Thibodeau","sequence":"additional","affiliation":[{"name":"D\u00e9partement de microbiologie, infectiologie et immunologie, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Laboratoire d\u2019immunologie mol\u00e9culaire, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Qu\u00e9bec,","place":["Canada"]},{"name":"Institut Courtois d\u2019innovation biom\u00e9dicale, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, 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