The ESCRT pathway and HIV-1 budding.
HIV-1 Gag engages components of the ESCRT (endosomal sorting complex required for transport) pathway via so-called L (late-assembly) domains to promote virus budding. Specifically, the PTAP (Pro-Thr-Ala-Pro)-type primary L domain of HIV-1 recruits ESCRT-I by binding to Tsg101 (tumour susceptibility gene 101), and an auxiliary LYPX(n)L (Leu-Tyr-Pro-Xaa(n)-Leu)-type L domain recruits the ESCRT-III-binding partner Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X]. The structurally related CHMPs (charged multivesicular body proteins), which form ESCRT-III, are kept in an inactive state through intramolecular interactions, and become potent inhibitors of HIV-1 budding upon removal of an autoinhibitory region. In the absence of the primary L domain, HIV-1 budding is strongly impaired, but can be efficiently rescued through the overexpression of Alix. This effect of Alix depends on its ability to interact with CHMP4, suggesting that it is the recruitment of CHMPs that ultimately drives virus release. Surprisingly, HIV-1 budding defects can also be efficiently corrected by overexpressing Nedd (neural-precursor-cell-expressed developmentally down-regulated) 4-2s, a member of a family of ubiquitin ligases previously implicated in the function of PPXY (Pro-Pro-Xaa-Tyr)-type L domains, which are absent from HIV-1. At least under certain circumstances, Nedd4-2s stimulates the activity of PTAP-type L domains, raising the possibility that the ubiquitin ligase regulates the activity of ESCRT-I.
Usami
Yoshiko
Y
Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Popov
Sergei
S
Popova
Elena
E
Inoue
Michio
M
Weissenhorn
Winfried
W
G Göttlinger
Heinrich
H
D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D011485:Protein Binding; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; D033921:Vesicular Transport Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases