PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons.
Impaired ciliary protein transport in olfactory sensory neurons (OSNs) leads to anosmia, and is a newly recognized clinical manifestation of a class of human disorders called ciliopathies. Surprisingly little is known regarding the mechanisms controlling trafficking to this unique neuronal compartment. Here, we show a novel role for phosphofurin acidic cluster-sorting protein 1 (PACS-1) in the ciliary trafficking of the olfactory cyclic-nucleotide-gated (CNG) channel. PACS-1 is an intracellular sorting protein that mediates its effects through the binding of acidic clusters on cargo protein. This interaction is dependent on CK2 phosphorylation of both PACS-1 and its cargo. We show that CNGB1b contains two putative PACS-1 binding sites, which are phosphorylated by the serine/threonine protein kinase, CK2. Additionally, we show that PACS-1 is expressed in OSNs and interacts in complex with the CNG channel. CK2 inhibition in native OSNs causes a loss of CNG channel from cilia and subsequent olfactory dysfunction, while adenoviral expression of mutant PACS-1 causes similar mislocalization. These results provide a mechanism for the subunit-dependent ciliary trafficking of the CNG channel and offer insight into the mechanisms of ciliary transport.
Jenkins
Paul M
PM
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-5632, USA.
Zhang
Lian
L
Thomas
Gary
G
Martens
Jeffrey R
JR
D000409:Alanine / Q000235:genetics; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism; D002461:Cell Line, Transformed; D002923:Cilia / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000145:classification / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009831:Olfactory Mucosa / Q000166:cytology*; D010766:Phosphorylation / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000502:physiology*; D012694:Serine / Q000235:genetics; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*
C405354:4,5,6,7-tetrabromobenzotriazole; D054815:Cyclic Nucleotide-Gated Cation Channels; D004791:Enzyme Inhibitors; C491914:PACS1 protein, human; D021122:Protein Subunits; D012333:RNA, Messenger; D014230:Triazoles; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins; D012694:Serine; D047390:Casein Kinase II; D000409:Alanine