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). A 2 TMS domain in these proteins may be related to those in family 8.A.115 (preliminary observation).
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). IFITM proteins broadly inhibit the entry of diverse pathogenic viruses, including Influenza A virus (IAV), Zika virus, HIV-1, and SARS coronaviruses by inhibiting virus-cell membrane fusion (Rahman et al. 2022).
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:
The interferon-induced transmembrane protein, IFITM1 (CD225, IFI17), of 125 aas and 2 TMSs (Li et al. 2015). IFITM3 accumulation at the sites of virus fusion is a prerequisite for its antiviral activity, and this protein traps viral fusion at a hemifusion stage by preventing the formation of fusion pores. The ability to utilize alternative endocytic pathways for entry confers IFITM3-resistance to otherwise sensitive viruses (Suddala et al. 2019). The Na+/taurocholate co-transporting polypeptide (NTCP, SLC10A1) is both a physiological bile acid transporter and the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Virus entry via endocytosis of the virus/NTCP complex involves co-factors. It is active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (Shi et al. 2021). IFITMs mediate protein abundance as it regulates the expression of viral and oncogenic proteins (Gómez-Herranz et al. 2022). IFITM1 enhances cholesterol transport to the Golgi to accumulate cholesterol at Golgi-derived replication sites, providing a novel mechanism by which IFITM1 enables efficient genome replication of non-enveloped RNA virus (Ishikawa-Sasaki et al. 2023).
Animals
IFITM1 of Homo sapiens
Interferon-induced transmembrane protein 2, IFITM2, is of 132 aas with 2 TMSs. Exosome-mediated transport of IFITM2 to dendridic cells inhibits IFNalpha (IFNα) pathway activation and blocks anti-hepatitis B virus (HBV) efficacy of exogenous IFNalpha (Shi et al. 2019). IFITMs are members of the dispanin/CD225 family that act as broad viral inhibitors by preventing viral-to-cellular membrane fusion (Zhong et al. 2022).
IFITM2 of Homo sapiens
IFITM3 or IFM3 of 133 aas and 2 TMSs, one at residies 60 80, and one C-terminal. It participates in the defense against viral infections (López-Jiménez et al. 2018). It plays a role in the structural stability and function of vacuolar ATPase (V-ATPase), 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 (Brass et al. 2009). IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry, underscoring the importance of cholesterol in virus infection (Amini-Bavil-Olyaee et al. 2013). The palmitoyltransferase ZDHHC20 enhances IFITM3 palmitoylation and antiviral activity (McMichael et al. 2017). mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3 (Shi et al. 2018). IFITM3 directly engages and shuttles incoming viruses to lysosomes. This trafficking is specific to restricted viruses, requires S-palmitoylation and is abrogated in loss-of-function mutants (Spence et al. 2019). Residues F75 and F78 are critical for antiviral activity, but these residues are dispensable for IFITM3 membrane localization and IFITM3/IFITM3 interactions (Winkler et al. 2019). IFITM3 reduces retroviral envelope abundance and function and is counteracted by glycoGag (Ahi et al. 2020). IFITM3 trafficking and turnover are regulated by the VCP/p97 ATPase (Wu et al. 2020). IFN-induced antiviral protein disrupts intracellular cholesterol homeostasis and inhibits the entry of viruses to the host cell cytoplasm by preventing viral fusion with cholesterol depleted endosomes. It may inactivate new enveloped viruses which bud out of the infected cell, by letting them go out with a cholesterol depleted membrane. It is active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (Narayana et al. 2015, Shi et al. 2021, Zang et al. 2020). IFITM3 is an NTCP co-factor that affects infection with hepatitis B and D viruses (HBV and HDV) in NTCP-expressing hepatoma cells. A direct interaction (PPI) between IFITM3 and NTCP has been demonstrated (Palatini et al. 2022). Cholesterol binds the amphipathic helix of IFITM3 to regulate its antiviral activity (Rahman et al. 2022). IFITM proteins broadly inhibit the entry of diverse pathogenic viruses, including Influenza A virus (IAV), Zika virus, HIV-1, and SARS coronaviruses by inhibiting virus-cell membrane fusion (Rahman et al. 2022). Inhibition of IAV entry by IFITM3 is associated with its ability to promote cellular membrane rigidity via the amphipathic helix found in the intramembrane domain (IMD) of IFITM3. The IFITM-3 (rs12252) variant is involved in HIV-1 mother-to-child transmission susceptibility (Leandro et al. 2023). IFITM1 enhances nonenveloped viral RNA replication by facilitating cholesterol transport to the Golgi (Ishikawa-Sasaki et al. 2023). IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion (Klein et al. 2023). Interferon-induced transmembrane proteins (IFITM) modulate cell permeability of diverse linked chemotypes (PMID 36546854). IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma (Jeong et al. 2024).
IFITM3 of Homo sapiens
IFITM5, Bril, Fragilis4 of 134 aas and 2 TMSs. The human ortholog shows abnormalities comprised deficient TGFbeta and P53 signal pathways as well as cell cycle pathway activation, and a potentially new driver mutation in the interferon induced transmembrane protein 5 (IFITM5) (Sun et al. 2023).
IFITM5 of Mus musculus
Dispanin A2b of 107 aas and 2 TMSs
Dispanin of Torpedo marmorata (marbled electric ray)
The proline-rich transmembrane protein of 340 aas, PRRT2 (Liu et al. 2016) belongs to the Dispanin (formerly the DUF4190) superfamily. Mutations give rise to paroxysmal hypnogenic dyskinesia (PHD), which is considered to be a form of nocturnal frontal lobe epilepsy (NFLE) (Erro et al. 2017). PRRT2 is the single causative gene for a group of paroxysmal syndromes of infancy, including epilepsy, paroxysmal movement disorders, and migraine (Robertson et al. 2019). Rossi et al. 2016 showed that PRRT2 is a type II transmembrane protein in which only the second hydrophobic segment spans the plasma membrane; the first one is associated with the internal surface of the membrane and forms a helix-loop-helix structure without crossing it. The large proline-rich N-terminal domain is localized intracellularly, and only the short C terminus is extracellular. PRRT2 interacts with the Src homology 3 domain-bearing protein, Intersectin 1, an intracellular protein involved in synaptic vesicle cycling. PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity (Fruscione et al. 2018). It interacts with several presynaptic proteins and voltage-gated Na+ channels. Several PRRT2 mutations are the main causes of a wide and heterogeneous spectrum of paroxysmal disorders with a loss-of-function pathomechanism as noted above. The highest expression levels of PRRT2 in brain occurs in cerebellar granule cells (GCs), and cerebellar dysfunctions participate in the dyskinetic phenotype of PRRT2 knockout (KO) mice. Binda et al. 2021 have investigated the effects of PRRT2 deficiency on the intrinsic excitability of GCs. They showed that PRRT2 KO primary GCs display increased expression of Na+ channels, increased amplitude of Na+ currents and increased length of the axon initial segment, leading to an overall enhancement of intrinsic excitability. In acute PRRT2 KO cerebellar slices, GCs were more prone to action potential discharge in response to mossy fiber activation and exhibited an enhancement of transient and persistent Na+ currents, in the absence of changes at the mossy fiber-GC synapses. Thus, a key role of PRRT2 expressed in GCs in the physiological regulation of the excitatory input to the cerebellum is consistent with a major role of a cerebellar dysfunction in the pathogenesis of the PRRT2-linked paroxysmal pathologies (Binda et al. 2021; Landolfi et al. 2021), especially paroxysmal kinesigenic dyskinesia (Ji et al. 2021). PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels (Ferrante et al. 2021). Self-limited familial infantile epilepsy (SFIE) is largely associated with variants in PRRT2, and antiepileptic drugs for SFIE have been discussed (Zhao et al. 2021). PRRT2 deficiency facilitates the induction of cerebellar spreading depolarization, and inhibition of cerebellar spreading depolarization prevents the occurrence of dyskinetic movements (Lu et al. 2021). SynDIG4 and PRRT1 act as typical AMPAR auxiliary proteins, while PRRT2 functions at presynaptic sites to regulate synaptic vesicle dynamics and is the causative gene for neurological paroxysmal disorders in humans (Dίaz 2021). PRRT2 specifically binds to GluA1 but has no effect on AMPA receptor-mediated synaptic transmission (Feng et al. 2022). For individuals with PRRT2-associated infantile epilepsy, sodium channel blockers are associated with reduced seizure frequency, but levetiracetam is not (Döring et al. 2022). PRRT2 is the single causative gene for pleiotropic paroxysmal syndromes including epilepsy, kinesigenic dyskinesia, episodic ataxia and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich amino-terminal cytoplasmic region. PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na+ channels Nav1.2 and Nav1.6, but not Nav1.1. PRRT2 is a dual-domain protein in which the NH2-terminal cytoplasmic region acts as a binding antenna for Na+ channels, while the COOH-terminal membrane domain regulates channel exposure on the membrane (Franchi et al. 2023). Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels (Sterlini et al. 2023).
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PRRT2 of Homo sapiens
Uncharacterized protein of 156 aas and 2 TMSs.
UP of Actinokineospora spheciospongiae
Uncharacterized protein of 186 aas and 2 TMSs.
UP of Helobdella robusta (Californian leech)
Uncharacterized protein of 113 aas and 2 TMSs.
UP of Leuconostoc kimchii
Synapse differentiation-inducing gene protein 1, SynDIG1 or TMEM90B, of 258 aas and 2 TMSs. Regulates AMPA receptor content at nascent synapses, and plays a role in postsynaptic development and maturation (Kalashnikova et al. 2010). Palmitoylation of SynDIG1 is regulated by neuronal activity, and plays a critical role in regulating its stability, subcellular localization and function (Kaur et al. 2016). SynDIG1 regulates the maturation of excitatory synapse structure and function (Chenaux et al. 2016; Kirk et al. 2016). SynDIG4 and PRRT1 act as typical AMPAR auxiliary proteins, while PRRT2 functions at presynaptic sites to regulate synaptic vesicle dynamics and is the causative gene for neurological paroxysmal disorders in humans (Dίaz 2021).
SynDIG1 of Homo sapiens
SynDIG4, Prrt1 or Ng5 of 306 aas and 2 TMSs. Associates with and regulates both AMPA and GluA1 receptors (Kirk et al. 2016). It regulates basal and plasticity-induced AMPA receptor trafficking (Troyano-Rodriguez et al. 2019). SynDIG4 and PRRT1 act as typical AMPAR auxiliary proteins, while PRRT2 functions at presynaptic sites to regulate synaptic vesicle dynamics and is the causative gene for neurological paroxysmal disorders in humans (Dίaz 2021).
SynDIG4 of Mus musculus (Mouse)
Uncharacterized tumor suppressor candidate 5-like protein of 115 aas and 2 TMSs
UP of Strongylocentrotus purpuratus (Purple sea urchin)
Transmembrane protein 91, TMEM91 of 172 aas and 2 TMSs.
TMEM91 of Homo sapiens
Uncharacterized protein of 141 aas and 2 TMSs. Contains a 5 aa repeat: GYGQP in the N-termina 50 aas.
UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)
Uncharacterized interferon-induced transmembrane-like protein of 133 aas and 2 TMSs
Interferon-induced transmembrane protein of
Nocardiopsis dassonvillei (Actinomadura dassonvillei)
Uncharacterized protein of 126 aas and 2 TMSs
UP of Gordonia araii
Uncharacterized protein of 183 aas and 2 TMSs
UP of Mycobacterium avium
Uncharacterized protein of 201 aas and 2 TMSs
UP of Clostridium leptum
Uncharacterized protein of 179 aas and 2 TMSs
UP of Porphyromonas endodontalis