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2 results on '"Geisler, Carsten"'

1. Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells

Author

Boding, Lasse, Hansen, Ann K., Johansen, Bo B., Braunstein, Thomas H., Bonefeld, Charlotte M., Kongsbak, Martin, Jensen, Benjamin A. H., Woetmann, Anders, Thomsen, Allan R., Ødum, Niels, von Essen, Marina R., Geisler, Carsten, MERONI, GERMANA, Boding, Lasse, Hansen, Ann K., Meroni, Germana, Johansen, Bo B., Braunstein, Thomas H., Bonefeld, Charlotte M., Kongsbak, Martin, Jensen, Benjamin A. H., Woetmann, Ander, Thomsen, Allan R., Ødum, Niel, von Essen, Marina R., and Geisler, Carsten

Subjects
Cytotoxicity, Immunologic, Mice, Knockout, Cytotoxicity, Granule exocytosis, Midline 1, T cells, Reverse Transcriptase Polymerase Chain Reaction, Secretory Vesicles, Ubiquitin-Protein Ligases, Blotting, Western, Proteins, hemic and immune systems, chemical and pharmacologic phenomena, Mice, Transgenic, Granule exocytosi, Flow Cytometry, Exocytosis, Mice, Animals, T-Lymphocytes, Cytotoxic
Abstract

Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity.

Published
2013

2. MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells

Author

Trine B. Levring, Carsten Geisler, Germana Meroni, Lasse Boding, Ann Kathrine Hansen, Niels Ødum, Charlotte M. Bonefeld, Anders Woetmann, Boding, Lasse, Hansen, Ann K., Meroni, Germana, Levring, Trine B., Woetmann, Ander, Ødum, Niel, Bonefeld, Charlotte M., and Geisler, Carsten

Subjects
Microbiology (medical), Cytotoxic T cell, Ubiquitin-Protein Ligases, Cytotoxic T cells, chemical and pharmacologic phenomena, Cytoplasmic Granules, Exocytosis, Exocytosi, Pathology and Forensic Medicine, Interferon-gamma, Mice, Animals, Immunology and Allergy, Midline 2, Cytotoxicity, Midline 1, Mice, Knockout, Lytic granule, biology, Lytic granules, Granule (cell biology), Proteins, hemic and immune systems, General Medicine, Transfection, Up-Regulation, Ubiquitin ligase, Cell biology, Mice, Inbred C57BL, CTL, Lytic cycle, biology.protein, Microtubule-Associated Proteins, 2734, T-Lymphocytes, Cytotoxic, Transcription Factors
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.

Published
2015

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