Abstract
PACS-1 is a cytosolic protein involved in controlling the correct subcellular localization of integral membrane proteins that contain acidic cluster sorting motifs, such as furin and human immunodeficiency virus type 1 (HIV-1) NEF: We have now investigated the interaction of PACS-1 with heterotetrameric adaptor complexes. PACS-1 associates with both AP-1 and AP-3, but not AP-2, and forms a ternary complex between furin and AP-1. A short sequence within PACS-1 that is essential for binding to AP-1 has been identified. Mutation of this motif yielded a dominant-negative PACS-1 molecule that can still bind to acidic cluster motifs on cargo proteins but not to adaptor complexes. Expression of dominant-negative PACS-1 causes a mislocalization of both furin and mannose 6-phosphate receptor from the trans-Golgi network, but has no effect on the localization of proteins that do not contain acidic cluster sorting motifs. Furthermore, expression of dominant-negative PACS-1 inhibits the ability of HIV-1 Nef to downregulate MHC-I. These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Protein Complex 3
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Adaptor Protein Complex alpha Subunits
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Adaptor Protein Complex delta Subunits
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Adaptor Proteins, Vesicular Transport
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Amino Acid Motifs / physiology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Down-Regulation / drug effects
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Furin
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Gene Expression
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Gene Products, nef / antagonists & inhibitors
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Gene Products, nef / metabolism
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Genes, Dominant
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Glutathione Transferase / genetics
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Humans
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Membrane Proteins / metabolism
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Monomeric Clathrin Assembly Proteins*
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Mutagenesis, Site-Directed
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Protein Binding / physiology
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Protein Transport / physiology
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Receptor, IGF Type 2
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Recombinant Fusion Proteins / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Subtilisins / metabolism
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Transcription Factors / metabolism
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Transfection
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Vesicular Transport Proteins
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trans-Golgi Network / metabolism
Substances
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AP3D1 protein, human
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Adaptor Protein Complex 3
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Adaptor Protein Complex alpha Subunits
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Adaptor Protein Complex delta Subunits
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Adaptor Proteins, Vesicular Transport
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Carrier Proteins
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Gene Products, nef
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Membrane Proteins
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Monomeric Clathrin Assembly Proteins
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PACS1 protein, human
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Pacs1 protein, mouse
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Receptor, IGF Type 2
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Recombinant Fusion Proteins
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Recombinant Proteins
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Transcription Factors
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Vesicular Transport Proteins
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clathrin assembly protein AP180
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Glutathione Transferase
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Subtilisins
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Furin