RT Journal Article
SR Electronic
T1 Physiological Substrates and Ontogeny-Specific Expression of the Ubiquitin Ligases MARCH1 and MARCH8
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.15.439921
DO 10.1101/2021.04.15.439921
A1 Patrick Schriek
A1 Haiyin Liu
A1 Alan C. Ching
A1 Pauline Huang
A1 Nishma Gupta
A1 Kayla R. Wilson
A1 MinHsuang Tsai
A1 Yuting Yan
A1 Christophe F. Macri
A1 Laura F. Dagley
A1 Giuseppe Infusini
A1 Andrew I. Webb
A1 Hamish McWilliam
A1 Satoshi Ishido
A1 Justine D. Mintern
A1 Jose A. Villadangos
YR 2021
UL http://biorxiv.org/content/early/2021/04/18/2021.04.15.439921.abstract
AB MARCH1 and MARCH8 are ubiquitin ligases that control the expression and trafficking of critical immunoreceptors. Understanding of their function is hampered by three major knowledge gaps: (i) it is unclear which cell types utilize these ligases; (ii) their level of redundancy is unknown; and (iii) most of their putative substrates have been described in cell lines, often overexpressing MARCH1 or MARCH8, and it is unclear which substrates are regulated by either ligase in vivo. Here we address these questions by systematically analyzing the immune cell repertoire of MARCH1- or MARCH8-deficient mice, and applying unbiased proteomic profiling of the plasma membrane of primary cells to identify MARCH1 and MARCH8 substrates. Only CD86 and MHC II were unequivocally identified as immunoreceptors regulated by MARCH1 and MARCH8, but each ligase carried out its function in different tissues. MARCH1 regulated MHC II and CD86 in professional and “atypical” antigen presenting cells of hematopoietic origin, whereas MARCH8 only operated in non-hematopoietic cells. Our results reveal that the range of cells constitutively endowed with antigen-presentation capacity is wider than generally appreciated. They also establish MARCH1 and MARCH8 as specialized regulators of CD4+ T cell immunity in two ontogenically distinct cellular compartments.Competing Interest StatementThe authors have declared no competing interest.