PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic.
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.
Crump
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CM
Vollum Institute, L-474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA.
Xiang
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Y
Thomas
L
L
Gu
F
F
Austin
C
C
Tooze
S A
SA
Thomas
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G
D033963:Adaptor Protein Complex 3; D033965:Adaptor Protein Complex alpha Subunits; D033981:Adaptor Protein Complex delta Subunits; D033942:Adaptor Proteins, Vesicular Transport; D020816:Amino Acid Motifs / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D045683:Furin; D015870:Gene Expression; D015693:Gene Products, nef / Q000037:antagonists & inhibitors / Q000378:metabolism; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D034041:Monomeric Clathrin Assembly Proteins; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013381:Subtilisins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins; D021601:trans-Golgi Network / Q000378:metabolism
C491904:AP3D1 protein, human; D033963:Adaptor Protein Complex 3; D033965:Adaptor Protein Complex alpha Subunits; D033981:Adaptor Protein Complex delta Subunits; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D015693:Gene Products, nef; D008565:Membrane Proteins; D034041:Monomeric Clathrin Assembly Proteins; C491914:PACS1 protein, human; C491913:Pacs1 protein, mouse; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; C439023:clathrin assembly protein AP180; D005982:Glutathione Transferase; D013381:Subtilisins; D045683:Furin