We have recently shown that the E3 ubiquitin ligase midline 1 (MID1) is upregulated in murine cytotoxic lymphocytes (CTL), where it controls exocytosis of lytic granules and the killing capacity. Accordingly, CTL from MID1 knock-out (MID1-/- ) mice have a 25-30% reduction in exocytosis of lytic granules and cytotoxicity compared to CTL from wild-type (WT) mice. We wondered why the MID1 gene knock-out did not affect exocytosis and cytotoxicity more severely and speculated whether MID2, a close homologue of MID1, might partially compensate for the loss of MID1 in MID1-/- CTL. Here, we showed that MID2, like MID1, is upregulated in activated murine T cells. Furthermore, MID1-/- CTL upregulated MID2 two-twenty-fold stronger than CTL from WT mice, suggesting that MID2 might compensate for MID1. In agreement, transfection of MID2 into MID1-/- CTL completely rescued exocytosis of lytic granules in MID1-/- CTL, and vice versa, knock-down of MID2 inhibited exocytosis of lytic granules in both WT and MID1-/- CTL, demonstrating that both MID1 and MID2 play a central role in the regulation of granule exocytosis and that functional redundancy exists between MID1 and MID2 in CTL.
Titolo: | MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells |
Autori: | |
Data di pubblicazione: | 2015 |
Rivista: | |
Abstract: | We have recently shown that the E3 ubiquitin ligase midline 1 (MID1) is upregulated in murine cytotoxic lymphocytes (CTL), where it controls exocytosis of lytic granules and the killing capacity. Accordingly, CTL from MID1 knock-out (MID1-/- ) mice have a 25-30% reduction in exocytosis of lytic granules and cytotoxicity compared to CTL from wild-type (WT) mice. We wondered why the MID1 gene knock-out did not affect exocytosis and cytotoxicity more severely and speculated whether MID2, a close homologue of MID1, might partially compensate for the loss of MID1 in MID1-/- CTL. Here, we showed that MID2, like MID1, is upregulated in activated murine T cells. Furthermore, MID1-/- CTL upregulated MID2 two-twenty-fold stronger than CTL from WT mice, suggesting that MID2 might compensate for MID1. In agreement, transfection of MID2 into MID1-/- CTL completely rescued exocytosis of lytic granules in MID1-/- CTL, and vice versa, knock-down of MID2 inhibited exocytosis of lytic granules in both WT and MID1-/- CTL, demonstrating that both MID1 and MID2 play a central role in the regulation of granule exocytosis and that functional redundancy exists between MID1 and MID2 in CTL. |
Handle: | http://hdl.handle.net/11368/2847809 |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1111/apm.12402 |
Appare nelle tipologie: | 1.1 Articolo in Rivista |
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