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8.A.58 The Dispanin (Dispanin) Family 

The IFN-induced antiviral proteins disrupt intracellular cholesterol homeostasis and inhibit the entry of viruses to the host cell cytoplasm by preventing viral fusion with cholesterol depleted endosomes. They may inactivate new enveloped viruses and are active against multiple viruses, including influenza A virus, SARS coronavirus (SARS-CoV), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), herpes virus and vesicular stomatitis virus (VSV). They can inhibit influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry, SARS-CoV S protein-mediated viral entry and VSV G protein-mediated viral entry (Narayana et al. 2015). They also play critical roles in the structural stability and function of vacuolar ATPases (v-ATPases) by establishing physical contact with the v-ATPase of endosomes which is required for the function of the v-ATPase to lower the pH in phagocytic endosomes, thus establishing an antiviral state (Kim et al. 2012).

Interferon-induced transmembrane (2 TMSs) proteins (IFITMs), collectively called dispanins, broadly inhibit virus infections, particularly at the viral entry level. However, despite this shared ability to inhibit fusion, IFITMs differ in the potency and breadth of viruses restricted. Differences in the range of viruses restricted by IFITM1 are regulated by a C-terminal non-canonical dibasic sorting signal KRXX that suppresses restriction of some viruses by governing its intracellular distribution (Li et al. 2015).  Replacing the two basic residues with alanine (KR/AA) increased restriction of jaagsiekte sheep retrovirus and 10A1 amphotropic murine leukemia virus. Deconvolution microscopy revealed an altered subcellular distribution for KR/AA, with fewer molecules in LAMP1-positive lysosomes balanced by increased levels in CD63-positive multivesicular bodies, where jaagsiekte sheep retrovirus pseudovirions are colocalized. IFITM1 binds to cellular adaptor protein complex 3 (AP-3), an association that is lost when the dibasic motif is altered. Although knockdown of AP-3 itself decreases some virus entry, expression of parental IFITM1, but not its KR/AA mutant, potentiates inhibition of viral infections in AP-3 knockdown cells. IFITM1 adopts more than one membrane topology co-existing in cellular membranes. Because the C-terminal dibasic sorting signal is unique to human IFITM1, a species- and virus-specific antiviral effect of IFITMs may be novel and unique (Li et al. 2015).

Modulation of AMPA receptor (AMPAR) contents at synapses is thought to be an underlying molecular mechanism of memory and learning. AMPAR content at synapses is highly plastic and is regulated by numerous AMPAR accessory transmembrane proteins such as TARPs, cornichons, and CKAMPs. SynDIG (synapse differentiation-induced gene) defines a family of four genes (SynDIG1-4) expressed in distinct and overlapping patterns in the brain (Kirk et al. 2016). SynDIG1 is a transmembrane AMPAR-associated protein that regulates synaptic strength. The related protein, SynDIG4, [also known as Prrt1 (proline-rich transmembrane protein 1)] is a component of AMPAR complexes, but SynDIG1 and SynDIG4 have distinct yet overlapping patterns of expression in the central nervous system, with SynDIG4 having especially prominent expression in the hippocampus and particularly within CA1. In contrast to SynDIG1 and other traditional AMPAR auxiliary subunits, SynDIG4 is de-enriched at the postsynaptic density and colocalizes with extrasynaptic GluA1 puncta in primary dissociated neuronal cultures. Thus, although SynDIG4 shares sequence similarity with SynDIG1, it may act through a different mechanism as an auxiliary factor for extrasynaptic GluA1-containing AMPARs (Kirk et al. 2016).

References associated with 8.A.58 family:

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López-Jiménez, J.J., D.I. Peña-Iñiguez, A.L. Fletes-Rayas, S.E. Flores-Martínez, J. Sánchez-Corona, R.C. Rosales-Gomez, and H. Montoya-Fuentes. (2018). Distribution of IFITM3 polymorphism (dbSNP: rs12252) in mestizo populations in four states of Mexico. Int J Immunogenet. [Epub: Ahead of Print] 29575524
McMichael, T.M., L. Zhang, M. Chemudupati, J.C. Hach, A.D. Kenney, H.C. Hang, and J.S. Yount. (2017). The palmitoyltransferase ZDHHC20 enhances interferon-induced transmembrane protein 3 (IFITM3) palmitoylation and antiviral activity. J. Biol. Chem. 292: 21517-21526. 29079573
Narayana SK., Helbig KJ., McCartney EM., Eyre NS., Bull RA., Eltahla A., Lloyd AR. and Beard MR. (2015). The Interferon-induced Transmembrane Proteins, IFITM1, IFITM2, and IFITM3 Inhibit Hepatitis C Virus Entry. J Biol Chem. 290(43):25946-59. 26354436
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