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Role of Transportin-SR2 in HIV-1 Nuclear Import

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Role of Transportin-SR2 in HIV-1 Nuclear Import viruses Review Role of Transportin-SR2 in HIV-1 Nuclear Import Maryam Tabasi, Ivan Nombela , Julie Janssens, Adrien P. Lahousse, Frauke Christ and Zeger Debyser * Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, Belgium; [email protected] (M.T.); [email protected] (I.N.); [email protected] (J.J.); [email protected] (A.P.L.); [email protected] (F.C.) * Correspondence: [email protected] Abstract: The HIV replication cycle depends on the interaction of viral proteins with proteins of the host. Unraveling host–pathogen interactions during the infection is of great importance for understanding the pathogenesis and the development of antiviral therapies. To date HIV uncoating and nuclear import are the most debated steps of the HIV-1 replication cycle. Despite numerous studies during past decades, there is still much controversy with respect to the identity and the role of viral and host factors involved in these processes. In this review, we provide a comprehensive overview on the role of transportin-SR2 as a host cell factor during active nuclear transport. Keywords: HIV-1; nuclear import; integrase; capsid; transportin-SR2; TRN-SR2; TNPO3; CPSF6 1. Introduction For productive infection, most DNA viruses and a few RNA viruses including Or- Citation: Tabasi, M.; Nombela, I.; thomyxoviridae and Retroviridae have to pass the barrier of the nuclear membrane to deliver Janssens, J.; Lahousse, A.P.; Christ, F.; their genome into the nucleus. Therefore, these viruses have evolved to exploit the com- Debyser, Z. Role of Transportin-SR2 plex machinery of nuclear trafficking [1,2]. Lentiviridae such as the human immunodefi- in HIV-1 Nuclear Import. Viruses 2021, 13, 829. https://doi.org/10.3390 ciency virus type 1 (HIV-1) are able to infect non-dividing cells like resting lymphocytes, /v13050829 macrophages and dendritic cells [1,3]. Classical studies showed that the nuclear envelope (NE) restricts access to the nucleus as only molecules smaller than 40 kDa or a diameter up Academic Editor: Francesca Di to 5 nm can passively diffuse through the NPC [4,5]. Interestingly a recent study showed Nunzio that the nuclear pore complex (NPC) represents a soft barrier to passive diffusion rather than a rigid barrier. However, the NPC contains FG domains with high net charge and low Received: 29 March 2021 hydropathy near the cytoplasmic end of the central channel that limit the passive diffusion Accepted: 2 May 2021 of macromolecules [6]. HIV-1 and other lentiviruses interact with the nuclear pores and Published: 4 May 2021 its associated receptors and proteins through an active nuclear import mechanism that remains poorly understood. Among all HIV-1 preintegration complex (PIC) components, Publisher’s Note: MDPI stays neutral the viral cDNA, integrase (IN), reverse transcriptase (RT), capsid (CA), matrix antigen with regard to jurisdictional claims in (MA) and viral protein R (Vpr) have all been proposed as the most important factor for HIV published maps and institutional affil- nuclear import [7–12]. Yet, the exact role of the viral determinants and host factors remains iations. a subject of debate. Here we summarize the most relevant and recent studies regarding the role of the host factor transportin-SR2 (TRN-SR2 also known as transportin-3 or TNPO3) in the HIV-1 nuclear import. Copyright: © 2021 by the authors. 2. The Mechanism of a Nuclear Import Licensee MDPI, Basel, Switzerland. The nucleus is surrounded by the NE, a double lipid bilayer, which ensures a tight This article is an open access article regulation of nuclear access and protection of the genetic material. Nucleocytoplasmic distributed under the terms and transport of macromolecules occurs through the NPC, which can be found with a density conditions of the Creative Commons of 3000–5000 NPCs/nucleus on the NE of a proliferating human cell [4,13]. The NPC and Attribution (CC BY) license (https:// the karyopherins or nuclear transport receptors are key players in the selective nuclear creativecommons.org/licenses/by/ transport of many molecules. They are essential in the nuclear import of molecules with 4.0/). Viruses 2021, 13, 829. https://doi.org/10.3390/v13050829 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 15 Viruses 2021, 13, 829 2 of 16 a size exceedinga size 40 exceedingkDa. Each 40NPC kDa. consists Each of NPC almost consists 1000 molecules of almost 1000of 30 moleculesdifferent nu- of 30 different cleoporins (NUPs),nucleoporins which are (NUPs), conserved which throug are conservedhout eukaryotes. throughout NUPs eukaryotes. are located NUPs in the are located in different partsthe of different the NPC parts including of the the NPC cyto includingplasmic filaments, the cytoplasmic the symmetric filaments, core, the and symmetric core, the nuclear basketand the (Figure nuclear 1). basketThey can (Figure be di1vided). They into can three be dividedgroups: into(1) structural three groups: NUPs, (1) structural (2) transmembraneNUPs, NUPs(2) transmembrane (referred as Poms),NUPs and (referred (3) FG-NUPs as Poms), that and contain (3) FG-NUPs extensive that re- contain exten- peats of phenylalanine-glycinesive repeats of phenylalanine-glycine (FG). The FG nucleoporins (FG). The such FG as nucleoporins Nup153 fill the such central as Nup153 fill the channel of thecentral NPC and channel form of a thehighly NPC dynami and formc barrier, a highly which dynamic determines barrier, both which the determines selec- both the tivity and theselectivity directionality and of the nuclear directionality transport. of nuclearIn addition, transport. the FG Inrepeats addition, act as the transi- FG repeats act as ent docking transientsites for importins docking sites and forexport importinsins [4,14]. and Nup358/RanBP2, exportins [4,14]. Nup358/RanBP2,which has been which has mapped exclusivelybeen mapped to the long exclusively cytoplasmic to the fi longlaments cytoplasmic of NPC, and filaments Nup153, of NPC,which and is part Nup153, which is part of the nuclear basket and associated with chromatin, are the two most important of the nuclear basket and associated with chromatin, are the two most important NUPs NUPs that have been associated with HIV-1 nuclear entry [15–19]. that have been associated with HIV-1 nuclear entry [15–19]. Figure 1. TheFigure nuclear 1. transportThe nuclear cycle. transport In the cycle. cytoplasm, In the cargo/importincytoplasm, cargo/importin complex formation complex formation is mediated is byme- the nuclear diated by the nuclear localization signal (NLS) of the cargo (upper left). In the nucleus the cargo is localization signal (NLS) of the cargo (upper left). In the nucleus the cargo is released upon binding of RanGTP to the released upon binding of RanGTP to the importin (lower panel). Next, the importin/RanGTP com- importin (lowerplex panel). is exported Next, to the the importin/RanGTP cytoplasm where complexthe GTPase is exported activating to protein the cytoplasm (GAP) hydrolyses where the GTPaseGTP to activating protein (GAP)GDP, hydrolyses which GTP subsequently to GDP,which leads subsequently to release of leadsimportin to release (upper of importinright). Ran (upper guanine right). nucleotide Ran guanine ex- nucleotide exchange factorchange (GEF) factor phosphorylates (GEF) phosphorylates Ran/GDP Ran/GDP in the nucleus. in the nucleus. The figure The isfigure created is created by https://app.biorender.com by (accessed on 22https://app.biorender.com March 2021). (accessed on 22 March2021). Nuclear importNuclear is a tightly import orchestrated is a tightly orchestratedprocess. The process.first step The in afirst nuclear step import in a nuclear is import is the recognitionthe and recognition binding andof the binding cargo ofto thethe cargoimportin to the in the importin cytosol. in Most the cytosol. importins Most importins belong to thebelong β-karyopherins to the β-karyopherins that interact thatwith interact the cargo’s with nuclear the cargo’s localization nuclear signal localization signal (NLS) to initiate(NLS) its totransport initiate into its transport the nucleu intos [4]. the The nucleus Ran GTPase [4]. The cycle Ran GTPase regulates cycle nuclear regulates nuclear import and contributesimport and directionality. contributes directionality. Ran binds to GTP Ran in binds the nucleus to GTP or in GDP the nucleus in the cy- or GDP in the tosol (Figure cytosol1). The (Figuredriving1 force). The for driving the cellul forcear distribution for the cellular is the distribution concentration is the of concentrationRan of guanine nucleotideRan guanine exchange nucleotide factors (GEF) exchange in the factors nucleus (GEF) and GTPase-activating in the nucleus and proteins GTPase-activating (GAP) in theproteins cytosol enabling (GAP) in directional the cytosol transfer enabling of directional NLS-containing transfer cargos of NLS-containing into the nu- cargos into cleus. In the thenext nucleus. step of nuclear In the nextimport, step the of importin-cargo nuclear import, complex the importin-cargo docks to the complexNPC docks to the NPC through the interaction with NUPs and passes the nuclear envelop. Inside the through the interaction with NUPs and passes the nuclear envelop. Inside the nucleus the nucleus the binding of Ran-GTP disassembles the importin-cargo complex and releases binding of Ran-GTP disassembles the importin-cargo complex and releases the cargo in Viruses 2021, 13, 829 3 of 16 the cargo in the cell nucleus. On the way back to the cytosol, Ran-GTP associated with importin-β is hydrolyzed to Ran-GDP to make the importin available for a new cycle of nuclear import [4,20]. 3. Transportin-SR2 Mediates Nuclear Import Nucleocytoplasmic transport is typically mediated by proteins of the karyopherinβ family [4]. These proteins share a similar structure consisting of an N-terminal Ran binding domain, a central NUP binding domain and a C-terminal cargo binding domain. Karyo- pherins recognize their cargo by a NLS or in the case of exportins by a nuclear export signal (NES).
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