iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I

Matteo Calligaris, Donatella P. Spanò, Simone Bonelli, Stephan A. Müller, Claudia Carcione, Danilo D’apolito, Giandomenico Amico, Monica Miele, Mariangela Di Bella, Giovanni Zito, Elisa Nuti, Armando Rossello, Carl P. Blobel, Stefan F. Lichtenthaler, Simone D. Scilabra

Research output: Contribution to journalArticlepeer-review


Proteolytic release of transmembrane proteins from the cell surface, the so called ectodomain shedding, is a key process in inflammation. Inactive rhomboid 2 (iRhom2) plays a crucial role in this context, in that it guides maturation and function of the sheddase ADAM17 (a disintegrin and metalloproteinase 17) in immune cells, and, ultimately, its ability to release inflammatory mediators such as tumor necrosis factor α (TNFα). Yet, the macrophage sheddome of iRhom2/ADAM17, which is the collection of substrates that are released by the proteolytic complex, is only partly known. In this study, we applied high-resolution proteomics to murine and human iRhom2-deficient macrophages for a systematic identification of substrates, and therefore functions, of the iRhom2/ADAM17 proteolytic complex. We found that iRhom2 loss suppressed the release of a group of transmembrane proteins, including known (e.g. CSF1R) and putative novel ADAM17 substrates. In the latter group, shedding of major histocompatibility complex class I molecules (MHC-I) was consistently reduced in both murine and human macrophages when iRhom2 was ablated. Intriguingly, it emerged that in addition to its shedding, iRhom2 could also control surface expression of MHC-I by an undefined mechanism. We have demonstrated the biological significance of this process by using an in vitro model of CD8+ T-cell (CTL) activation. In this model, iRhom2 loss and consequent reduction of MHC-I expression on the cell surface of an Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line dampened activation of autologous CTLs and their cell-mediated cytotoxicity. Taken together, this study uncovers a new role for iRhom2 in controlling cell surface levels of MHC-I by a dual mechanism that involves regulation of their surface expression and ectodomain shedding.

Original languageEnglish
Article number163
JournalCellular and Molecular Life Sciences
Issue number1
StatePublished - Dec 2024
Externally publishedYes


  • ADAM17
  • iRhom2
  • Macrophages
  • MHC class I molecules
  • Secretome


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