Abstract
Major histocompatibility complex class II (MHC II) expression and turn-over are regulated via its ubiquitination by the membrane associated RING-CH 1 (MARCH1) E3 ligase. Unexpectedly, we show that MHC II ubiquitination also impacts MHC I. Lack of MARCH1 in B cells and dendritic cells (DCs) resulted in a significant reduction in surface MHC I expression. This decrease was not directly caused by changes in MARCH1 ubiquitination of MHC I but indirectly by altered MHC II trafficking in the absence of its ubiquitination. Deletion of MHC II in March1-/- cells restored normal MHC I surface expression and replacement of wild type MHC II by a variant that could not be ubiquitinated caused a reduction in MHC I expression. Furthermore, these cells displayed inefficient presentation of peptide and protein antigen via MHC I to CD8+ T cells. In summary, we describe an unexpected intersection between MHC I and MHC II such that the surface expression of both molecules are indirectly and directly regulated by MARCH1 ubiquitination, respectively.
Highlights
Ubiquitination is a post-translational modification that acts as a sorting signal to deliver proteins to specific cellular destinations
In accordance with previous studies [8,9,11], we observed elevated surface major histocompatibility complex class II (MHC II) expression in isgMarch1 relative to isghBim (Fig 1). This is due to the role of membrane associated RING-CH 1 (MARCH1)-mediated ubiquitination in enhanced turnover and reduced surface expression of this receptor
We examined the possibility that reduced MHC I expression in MARCH1-deficient cells was caused indirectly by increased expression of bona fide MARCH1 substrates, MHC II
Summary
Ubiquitination is a post-translational modification that acts as a sorting signal to deliver proteins to specific cellular destinations. Ubiquitin attachment alters their traffic to and from the cell surface [1]. This occurs either by redirecting their route in the secretory pathway or via the regulation of endocytic trafficking. Surface expression and half-life of major histocompatibility complex class II (MHC II), the molecule responsible for CD4+ T cell antigen presentation and initiation of adaptive immunity, is controlled via ubiquitination [3,4]. We describe here that by ubiquitinating MHC II, MARCH1 promotes elevated MHC I surface expression that impacts both direct and cross-presentation by professional antigen presenting cells
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