Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86

• Published in: Nature communications Vol. 13; no. 1; pp. 1934 - 15
• Main Authors: Liu, Haiyin, Wilson, Kayla R., Firth, Ashley M., Macri, Christophe, Schriek, Patrick, Blum, Annabelle B., Villar, Javiera, Wormald, Samuel, Shambrook, Mitch, Xu, Bangyan, Lim, Hui Jing, McWilliam, Hamish E. G., Hill, Andrew F., Edgington-Mitchell, Laura E., Caminschi, Irina, Lahoud, Mireille H., Segura, Elodie, Herold, Marco J., Villadangos, Jose A., Mintern, Justine D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-04-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 14/63; 45/23; 49/109; 49/40; 631/250/21/1293; 631/250/21/324/1508; 631/250/2504/133/2505; 631/80/458/582; 64/60; 82/58; Adaptive immunity; Animals; Antigen presentation; Antigen-presenting cells; Antigens; B7-2 Antigen - metabolism; CD86 antigen; CRISPR; Dendritic Cells; Genomes; Histocompatibility Antigens Class II - metabolism; Humanities and Social Sciences; Immunity; Immunology; Immunoregulation; Lymphocytes; Lymphocytes B; Lymphocytes T; Macrophages; Major Histocompatibility Complex; Mice; Mice, Inbred C57BL; multidisciplinary; Proteins; Science; Science (multidisciplinary); Substrates; Thymus; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29524-w

The MARCH E3 ubiquitin (Ub) ligase MARCH1 regulates trafficking of major histocompatibility complex class II (MHC II) and CD86, molecules of critical importance to immunity. Here we show, using a genome-wide CRISPR knockout screen, that ubiquitin-like protein 3 (UBL3) is a necessary component of ubiquitination-mediated trafficking of these molecules in mice and in humans.
Ubl3
-deficient mice have elevated MHC II and CD86 expression on the surface of professional and atypical antigen presenting cells. UBL3 also regulates MHC II and CD86 in human dendritic cells (DCs) and macrophages. UBL3 impacts ubiquitination of MARCH1 substrates, a mechanism that requires UBL3 plasma membrane anchoring via prenylation. Loss of UBL3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation. In summary, we identify UBL3 as a conserved, critical factor in MARCH1-mediated ubiquitination with important roles in immune responses.
Regulated trafficking of major histocompatibility complex class II and CD86 is a prerequisite of antigen presenting cell functionality. Authors show here that ubiquitin-like protein 3 is critically involved in the ubiquitination process that controls trafficking, with wide-ranging immunological consequences.