Human T-cell lymphotropic virus type 1 (HTLV-1) is transmitted through a viral synapse and enters target cells via interaction with the glucose transporter GLUT1. Here, we show that Neuropilin-1 (NRP1), the receptor for semaphorin-3A and VEGF-A165 and a member of the immune synapse, is also a physical and functional partner of HTLV-1 envelope (Env) proteins. HTLV-1 Env and NRP1 complexes are formed in cotransfected cells, and endogenous NRP1 contributes to the binding of HTLV-1 Env to target cells. NRP1 overexpression increases HTLV-1 Env-dependent syncytium formation. Moreover, overexpression of NRP1 increases both HTLV-1 and HTLV-2 Env-dependent infection, whereas down-regulation of endogenous NRP1 has the opposite effect. Finally, overexpressed GLUT1, NRP1, and Env form ternary complexes in transfected cells, and endogenous NRP1 and GLUT1 colocalize in membrane junctions formed between uninfected and HTLV-1-infected T cells. These data show that NRP1 is involved in HTLV-1 and HTLV-2 entry, suggesting that the HTLV receptor has a multicomponent nature.Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (49). Unlike other retroviruses, free HTLV-1 virions are poorly infectious, with cellto-cell contact being the major route of viral transfer in vivo (14). The importance of intercellular contacts for efficient HTLV-1 transmission was highlighted by Bangham and collaborators, who showed that an essential determinant of HTLV-1 cell-cell spreading is the establishment of a viral synapse (21).On the viral side, HTLV-1 entry depends on the 46-kDa surface glycoprotein (SU), which is responsible for receptor recognition, and the 21-kDa transmembrane glycoprotein (TM), which triggers the fusion between viral and cellular membranes (32). Both proteins are produced by cleavage of the 61-kDa envelope (Env) precursor (42,46). Regions in the 313-amino-acid-long SU encompassing residues 100 and 200 were shown to be the targets of neutralizing antibodies (2,43,57). Consistent with these observations, we and others showed that mutations introduced in these regions reduce the ability of HTLV-1 Env to trigger syncytium formation and/or virus infection (11,12,48,52,59).Originally detected in CD4 ϩ T cells (50), HTLV-1 infects other cell types in vivo, including CD8 ϩ T cells, monocytes, endothelial cells, and dendritic cells (18,20,30,33). In contrast to this limited tropism in vivo, the HTLV receptor appears to be expressed in almost all cell lines. Moreover, the HTLV receptor is highly conserved in vertebrate species (41, 56). As a result of Env/receptor interactions, the HTLV-1 receptor is down-regulated or nonfunctional at the surface of chronically infected T cells (17,47). Cell fusion induced by HTLV-2, a closely related nonpathogenic retrovirus, is also prevented in chronically HTLV-1-infected T cells, demonstrating that HTLV-1 and HTLV-2 share the same receptor (55). Heparan sulfate proteoglycans have been reported to play a rol...
In basal adipocytes, glucose transporter 4 (GLUT4) is sequestered intracellularly by an insulin-reversible retention mechanism. Here, we analyze the roles of three GLUT4 trafficking motifs (FQQI, TELEY, and LL), providing molecular links between insulin signaling, cellular trafficking machinery, and the motifs in the specialized trafficking of GLUT4. Our results support a GLUT4 retention model that involves two linked intracellular cycles: one between endosomes and a retention compartment, and the other between endosomes and specialized GLUT4 transport vesicles. Targeting of GLUT4 to the former is dependent on the FQQI motif and its targeting to the latter is dependent on the TELEY motif. These two motifs act independently in retention, with the TELEY-dependent step being under the control of signaling downstream of the AS160 rab GTPase activating protein. Segregation of GLUT4 from endosomes, although positively correlated with the degree of basal retention, does not completely account for GLUT4 retention or insulin-responsiveness. Mutation of the LL motif slows return to basal intracellular retention after insulin withdrawal. Knockdown of clathrin adaptin protein complex-1 (AP-1) causes a delay in the return to intracellular retention after insulin withdrawal. The effects of mutating the LL motif and knockdown of AP-1 were not additive, establishing that AP-1 regulation of GLUT4 trafficking requires the LL motif. INTRODUCTIONInsulin regulation of glucose uptake into adipose and muscle is key for the disposal of dietary glucose. The facilitative glucose transporter 4 (GLUT4) mediates the effect of insulin on glucose transport. GLUT4 is constitutively active for hexose transport, and glucose uptake is regulated by insulin controlling the amount of GLUT4 in the plasma membrane (PM) (Huang and Czech, 2007). In basal adipocytes, GLUT4 is slowly exocytosed and rapidly endocytosed, and Ͻ5% of the total amount of GLUT4 is in the PM. Insulin signaling results in changes in GLUT4 trafficking parameters: GLUT4 exocytosis is accelerated, whereas GLUT4 endocytosis is inhibited, resulting in a net 10-to 15-fold increase of surface GLUT4 and glucose uptake.The effect of insulin on the fraction of GLUT4 in the PM of adipose and muscle cells reflects a specific regulation of GLUT4 trafficking rather than a general perturbation of membrane trafficking. Besides GLUT4, the only other protein whose amount in the PM is comparably regulated by insulin signaling is the insulin-responsive amino peptidase (IRAP) (Kandror et al., 1994;Keller et al., 1995;Garza and Birnbaum, 2000). The amounts of other proteins in the PM are only slightly affected by insulin. For example, the PM levels of the ubiquitously expressed GLUT1 and the transferrin receptor (TR) are only increased by approximately twofold upon insulin stimulation (Piper et al., 1991;Yang et al., 1992;Zeigerer et al., 2002).The effects of insulin on GLUT4 are cell-type-specific since insulin has a minor effect on the trafficking of GLUT4 ectopically expressed in fibroblast-like ce...
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