MPYS, a Novel Membrane Tetraspanner, Is Associated with Major Histocompatibility Complex Class II and Mediates Transduction of Apoptotic Signals

Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Medical and Research Center, Denver, CO 80206, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2008; 28(16):5014-26. DOI: 10.1128/MCB.00640-08
Source: PubMed


Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides
to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death.
MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction
of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response.
Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction
of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (∼140 amino acids)
with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol
lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of
the extracellular signal-regulated kinase signaling pathway.

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    • "An emerging theme of the action of these DNA sensors is that signaling pathways initiating from them are apparently converged on stimulator of interferon genes (STING, a.k.a. MITA, ERIS, or MPYS), a transmembrane protein in the endoplasmic reticulum (ER) (Ishikawa and Barber, 2008; Jin et al., 2008; Li et al., 2009; Sun et al., 2009; Zhong et al., 2008). STING-deficient cells display profound defects in producing IFN-b and other proinflammatory cytokines stimulated by herpes simplex virus 1 (HSV-1) or Listeria monocytogenes (Ishikawa et al., 2009). "
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    ABSTRACT: Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):919-933. DOI:10.1016/j.immuni.2014.11.011 · 21.56 Impact Factor
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    • "The activation of STING (also referred to as TMEM 173/ MPYS/MITA/ERIS) may involve direct association with cytosolic DNA species as well as with cyclic dinucleotides (cyclic diguanosine monophosphate [GMP] or AMP) generated directly from certain intracellular bacteria or via a DNA-binding protein cGAS (cGAMP synthase, also known as male abnormal 21 domain containing 1 [Mab-21 domain containing1/MB21D1] or C6orf150) (Burdette et al., 2011; Diner et al., 2013; Jin et al., 2008; Sun et al., 2009, 2013; Woodward et al., 2010; Zhong et al., 2008). However, following the detection of cytosolic DNA, cGAS utilizes GTP and ATP to generate noncanonical 2 0 to 5 0 cyclic GMP-AMP (cGAMP) rather than 3 0 to 5 0 canonical cyclic dinucleotide species generally generated by bacteria (Ablasser et al., 2013; Civril et al., 2013; Gao et al., 2013; Kranzusch et al., 2013; Zhang et al., 2013). "
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    ABSTRACT: Activation of the stimulator of interferon genes (STING) pathway by microbial or self-DNA, as well as cyclic dinucleotides (CDNs), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent proinflammatory disease by mechanisms that remain unknown. We demonstrate here that, after autophagy-dependent STING delivery of TANK-binding kinase 1 (TBK1) to endosomal/lysosomal compartments and activation of transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1), and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor AMP activated protein kinase (AMPK) and was elicited by CDNs generated by the cGAMP synthase, cGAS. Thus, although CDNs may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes.
    Cell 10/2013; 155(3). DOI:10.1016/j.cell.2013.09.049 · 32.24 Impact Factor
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    • "A number of cytosolic DNA sensor proteins have been proposed including DAI, DDX41, IFI16, Ku70, DHX9, DHX36, and AIM2 (for review see Keating et al., 2011) as well as RIG-I that detects AT-rich DNA in the form of polymerase III RNA transcripts (Ablasser et al., 2009; Chiu et al., 2009). Most recently, an important DNA sensor that stimulates type I interferon (IFN) by activating the endoplasmic reticulum protein STING (also known as MITA, MPYS, or ERIS [Ishikawa and Barber, 2008; Ishikawa et al., 2009; Jin et al., 2008; Sun et al., 2009; Zhong et al., 2008]) and then Tank-binding kinase 1 (TBK1) (Ishii et al., 2006; Stetson and Medzhitov, 2006) has been identified (Sun et al., 2012; Wu et al., 2013). The binding of free DNA to the newly described cGMP-AMP synthase (cGAS) leads to the production of a second messenger cyclic dinucleotide c[G(2 0 5 0 )pA(3 0 5 0 )p] (Gao et al., 2013), which binds to and activates STING, resulting in the activation of the cytosolic kinases IKKε and TBK1. "
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    ABSTRACT: Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation. Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN). Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity.
    Immunity 08/2013; 39(3). DOI:10.1016/j.immuni.2013.08.004 · 21.56 Impact Factor
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