TY - JOUR T1 - TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours. JF - Int J Biochem Cell Biol Y1 - 2016 A1 - Lazzari, Elisa A1 - Meroni, Germana AB -

TRIM32 is a member of the TRIpartite Motif family characterised by the presence of an N-terminal three-domain-module that includes a RING domain, which confers E3 ubiquitin ligase activity, one or two B-box domains and a Coiled-Coil region that mediates oligomerisation. Several TRIM32 substrates were identified including muscular proteins and proteins involved in cell cycle regulation and cell motility. As ubiquitination is a versatile post-translational modification that can affect target turnover, sub-cellular localisation or activity, it is likely that diverse substrates may be differentially affected by TRIM32-mediated ubiquitination, reflecting its multi-faceted roles in muscle physiology, cancer and immunity. With particular relevance for muscle physiology, mutations in TRIM32 are associated with autosomal recessive Limb-Girdle Muscular Dystrophy 2H, a muscle-wasting disease with variable clinical spectrum ranging from almost asymptomatic to wheelchair-bound patients. In this review, we will focus on the ability of TRIM32 to mark specific substrates for proteasomal degradation discussing how the TRIM32-proteasome axis may (i) be important for muscle homeostasis and for the pathogenesis of muscular dystrophy; and (ii) define either an oncogenic or tumour suppressive role for TRIM32 in the context of different types of cancer.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27458054?dopt=Abstract ER - TY - JOUR T1 - MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells. JF - APMIS Y1 - 2015 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Levring, Trine B A1 - Woetmann, Anders A1 - Ă˜dum, Niels A1 - Bonefeld, Charlotte M A1 - Geisler, Carsten KW - Animals KW - Cytoplasmic Granules KW - Exocytosis KW - Interferon-gamma KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Microtubule-Associated Proteins KW - Proteins KW - T-Lymphocytes, Cytotoxic KW - Transcription Factors KW - Up-Regulation AB -

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.

VL - 123 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25924778?dopt=Abstract ER - TY - JOUR T1 - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells. JF - Eur J Immunol Y1 - 2014 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Johansen, Bo B A1 - Braunstein, Thomas H A1 - Bonefeld, Charlotte M A1 - Kongsbak, Martin A1 - Jensen, Benjamin A H A1 - Woetmann, Anders A1 - Thomsen, Allan R A1 - Odum, Niels A1 - von Essen, Marina R A1 - Geisler, Carsten KW - Animals KW - Blotting, Western KW - Cytotoxicity, Immunologic KW - Exocytosis KW - Flow Cytometry KW - Mice KW - Mice, Knockout KW - Mice, Transgenic KW - Proteins KW - Reverse Transcriptase Polymerase Chain Reaction KW - Secretory Vesicles KW - T-Lymphocytes, Cytotoxic AB -

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.

VL - 44 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25043946?dopt=Abstract ER -