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C-Terminal Tyrosine Phosphorylation of the Viral Matrix Protein Is a Key Regulator

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C-Terminal Tyrosine Phosphorylation of the Viral Matrix Protein Is a Key Regulator Cell, Vol. 80, 379-388, February 10, 1995, Copyright © 1995 by Cell Press HIV-1 Infection of Nondividing Cells: C-Terminal Tyrosine Phosphorylation of the Viral Matrix Protein Is a Key Regulator Philippe Gallay, Simon Swingler, Christopher Aiken, et al., 1992) that closely resembles the prototypic SV40 and Didier Trono large T antigen NLS (Kalderon et al., 1984). A peptide Infectious Disease Laboratory based on the MA NLS acts as a nuclear targeting se- The Salk Institute for Biological Studies quence when coupled to a heterologous protein in vitro 10010 North Torrey Pines Road (Bukrinsky et al., 1993a). In cells acutely infected with H IV-l, La Jolla, California 92037 MA was detected in fractions containing partially purified HIV-1 preintegration complexes (Bukrinsky et al., 1993b), as well as in the nucleus (Sharova and Bukrinskaya, 1991). Summary In the absence of a functional vpr gene, the critical role of the MA NLS is further revealed: vpr-MA-NLS double The HIV-1 matrix (MA) protei n contains two subcellular mutant viruses show a defect in nuclear import and, as a localization signals with opposing effects. A myristoy- result, have an impaired ability to infect nondividing cells lated N-terminus governs particle assembly at the such as macrophages (Bukrinsky et al., 1993a; Heinzinger plasma membrane, and a nucleophilic motif facilitates et al., 1994; von Schwedler et al., 1994). import of the viral preintegration complex into the nu- In addition to fulfilling this critical function at an early cleus of nondividing cells. Here, we show that myris- step of the infection process, MA also plays an essential toylation acts as the MA dominant targeting signal in role in virus morphogenesis. Indeed, a myristate residue HIV-1 producer cells. During virus assembly, a subset at the N-terminus of MA directs Gag to the plasma mem- of MA is phosphorylated on the C-terminal tyrosine by brane. This targeting is essential for the proper assembly a virion-associated cellular protein kinase. Tyrosine- of viral particles and for their release into the extracellular phosphorylated MA is then preferentially transported space (Varmus and Swanstrom, 1984). In the process, MA to the nucleus of target cells. An MA tyrosine mutant also recruits the envelope glycoprotein at the surface of virus grows normally in dividing cells, but is blocked virions (Yu et al., 1992a, 1992b; Dorfman et al., 1994). for nuclear import in terminally differentiated macro- Correspondingly, MA has been localized to the periphery phages. MA tyrosine phosphorylation thus reveals the of mature HIV-1 particles, bound to the inner leaflet of the karyophilic properties of this protein within the HIV-1 virus lipid bilayer (Gelderblom et al., 1987). preintegration complex, thereby playing a critical role Since the myristoylation signal and the N LS have oppos- for infection of nondividing cells. ing influences on the subcellular localization of MA, their respective effects must be tightly regulated. The present Introduction work reveals the mechanism of this regulation. We find that myristoylation acts as a dominant targeting signal for Retroviruses are single-stranded RNAviruses whose repli- MA in HIV-1 producer cells, preventing the NLS-mediated cation depends on the integration of a double-stranded nuclear import of the protein. We further demonstrate that DNA intermediate, termed the provirus, into the host cell a small subset of MA molecules undergo C-terminal tyro- genome. For oncoretroviruses, this process depends on sine phosphorylation at the time of particle assembly. Both cell proliferation (Humphries and Temin, 1972, 1974), be- membrane association and proteolytic cleavage of Gag cause the breakdown of the nuclear envelope at mitosis are necessary for this modification, which can be observed is necessary for bringing the viral preintegration complex in the absence of other viral proteins. Accordingly, tyrosine in contact with the cell chromosomes (Roe et al., 1993; phosphorylation can be observed when recombinant MA Lewis and Emerman, 1994). In contrast, human immuno- is exposed to cellular extracts, as well as viral lysates. deficiency virus type 1 (HIV-1) has the ability to infect non- Although only 1% of all MA molecules internalized by dividing cells (Lewis et al., 1992). This property is shared newly infected cells migrate to the nucleus, the majority with other lentiviruses and reflects the existence of deter- of those phosphorylated on tyrosine are rapidly translo- minants that govern the active transport of the viral preinte- cated to this compartment. Mutating the C-terminal tyro- gration complex through the nucleopore (Bukrinsky et al., sine of MA to phenylalanine does not alter Gag processing, 1992). It likely plays a crucial role in AIDS pathogenesis nor replication of the resulting virus in dividing cells, such because it allows the spread of HIV-1 in such critical tar- as activated T lymphocytes. However, in the absence of gets as terminally differentiated macrophages (Weinberg a functional vpr gene, the MA tyrosine mutant is profoundly et al., 1991). defective for growth in terminally differentiated macro- Two viral proteins, matrix (MA) and Vpr, have been phages, owing to a block in the nuclear import of the viral shown to participate in this process in a partly redundant preintegration complex. These results thus demonstrate manner (Bukrinsky et al., 1993a; Heinzinger et al., 1994; that tyrosine phosphorylation reveals the karyophilic func- von Schwedler et al., 1994). MA is the N-term inal cleavage tion of MA in the context of the HIV-1 preintegration com- product of the HIV-1 Gag precursor by the viral protease plex, thereby playing a crucial role for infection of nonpro- and contains a nuclear localization signal (NLS) (Myers liferating cells such as macrophages. Cell 380 Figure 1. Myristoylation Prevents the NLS- KK*~KLKH S, C ..... ~,,,J-C'~'~!! ! !! !!!!!iia~m m~I Mediated NuclearImport of HIV-1 MA in Pro- ducer Cells MA: (A) Schematic representationof MA variants TTK~LK. analyzed in these experiments. MAG2A/KK27Tr: A ~ iii~ ~|~ T~KLK* (B) MA,H~sand MA~, variantsare nonmyristoy- rated. [3H]myristate-labeledextracts from 293 CA: cells transfected with proviral constructs ex- CX pressing either wild-typeMA, or the two N-ter- WT MAG2A minus mutated forms of the protein (see [A]), were analyzed by immunoprecipitationwith MA-specific antibody. @ ~ ~ ~ tubulir (C) Subcellular localization of MA in trans- Irealrnent: -- fected cells. Cytoplasmic (CX) and nuclear (NX) fractions of 293 cells transfected with DNAs expressing the various forms of MA 1 2 3 4 5 6 1 2 3 4 5 6 7 1 2 3 4 5 6 shown in (A) (minus: mock) were analyzedby Western blotting, with antibodiesagainst MA (top), CA (middle), and tubulin (bottom). Wild- type MA (lane 2) is found exclusivelyin the cytoplasm, whereaslarge amounts of the two nonmyristoylatedforms of MA (lanes 3 and 5) migrate to the nucleus. Nucleartransport of nonmyristoylatedMA is greatly reduced by a mutationin the NLS (lanes4 and 6). CA and the tubulin control are restricted to the cytoplasm. (D) Wild-type MA is tightly bound to the plasmamembrane. 293 ceils expressingwild-type and a nonmyristoylatedform of MA were separated into plasmamembrane, cytosol, and nucleusfractions, followedby immunoprecipitationwith MA-specific antibodyand Western blotting. (E) Nuclearimport of nonmyristoylatedMA is blockedby NLS peptideand wheatgerm agglutinin(WGA), 293 cells expressingMAGu, were treated overnight as indicatedabove each lane (minus: mock). Nuclearfractions were then analyzedby immunoprecipitationwith MA-specific antibody, followed by Western blotting. The effect of WGA could be preventedby addition of N-acetylglucosamine,as described (Forbes, 1992). Results HIV-1 preintegration complex (Gulizia et al., 1994), as well as that of other karyophiles harboring a related signal (Mi- Myristoylation Prevents the NLS-Mediated chaud and Goldfarb, 1993). Finally, nuclear import of non- Transport of MA to the Nucleus myristoylated MA could be prevented by wheat germ ag- of HIV-1 Producer Cells glutinin (Figure 1E, lanes 5-7), a lectin that specifically Altered forms of the HIV-1 MA protein were generated in blocks transport through the nuclear pore (reviewed by the context of a full-length proviral construct (Figure 1A). Forbes, 1992). First, two nonmyristoylated variants were created, one by In these experiments, MA was expressed together with replacing the MA N-terminal glycine by alanine, the sec- the other products of the gag and pol genes, raising the ond by introducing six histidines at the proximal end of possibility that these additional polypeptides altered its Gag. Both mutations effectively prevented myristoylation localization. These studies were thus repeated with HIV-1- (Figure 1 B). N LS-defective versions of these proteins were derived constructs in which the sequence encoding wild- also derived by replacing two lysines in the NLS by threo- type or nonmyristoylated MA was immediately followed by nines, a change previously shown to abrogate the function a stop codon. The respective distribution of these proteins of this motif (von Schwedler et al., 1994). Cytoplasmic and was similar to that observed in the context of full-length nuclear extracts of cells transfected with these constructs precursors, indicating that MA subcellular targeting is in- were then analyzed by Western blotting (Figure 1C). Wild- dependent from other Gag and Pol proteins (data not type MA was found exclusively in the cytoplasm (Figure shown). 1C, lane 2), as was the viral capsid (CA); tubulin, a protein normally restricted to this compartment, sewed as a con- MA Molecules Imported to the Nucleus of Newly trol. Further separation of the cytoplasm in membrane and Infected Cells Are Myristoylated cytosol fractions revealed that myristoylated MA was asso- The above data indicate that MA has intrinsic nucleophilic ciated with the plasma membrane, as previously de- properties conferred by the NLS, but in virus producer scribed (Varmus and Swanstrom, 1984; Spearman et al., cells, these are masked by myristoylation. Yet, once HIV-1 1994) (Figure 1D, lanes 1-3).
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