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The Journal of Neuroscience, May 27, 2009, 29(21):6883-6896; doi:10.1523/JNEUROSCI.4723-08.2009

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Cellular/Molecular
UBXD4, a UBX-Containing Protein, Regulates the Cell Surface Number and Stability of {alpha}3-Containing Nicotinic Acetylcholine Receptors

Khosrow Rezvani,1 Yanfen Teng,1 Yaping Pan,1 John A. Dani,1,2 Jon Lindstrom,3 Eduardo A. García Gras,4 J. Michael McIntosh,5,6 and Mariella De Biasi1,2

1Department of Neuroscience and 2Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, 3Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, 4Centro de Salud y Medio Ambiente, Escuela de Ciencia y Tecnologia, Universidad de General San Martin, 1650 San Martin, Provincia de Buenos Aires, Argentina, and 5Departments of Psychiatry and 6Biology, University of Utah, Salt Lake City, Utah 84112

Correspondence should be addressed to Mariella De Biasi, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030. Email: debiasi{at}bcm.tmc.edu

Adaptor proteins are likely to modulate spatially and temporally the trafficking of a number of membrane proteins, including neuronal nicotinic acetylcholine receptors (nAChRs). A yeast two-hybrid screen identified a novel UBX-containing protein, UBXD4, as one of the cytosolic proteins that interact directly with the {alpha}3 and {alpha}4 nAChR subunits. The function of UBX-containing proteins is largely unknown. Immunoprecipitation and confocal microscopy confirmed the interaction of UBXD4 with {alpha}3-containing nAChRs ({alpha}3* nAChRs) expressed in HEK293 cells, PC12 cells, and rat cortical neurons. Overexpression of UBXD4 in differentiated PC12 cells (dPC12) increased nAChR cell surface expression, especially that of the {alpha}3β2 subtype. These findings were corroborated by electrophysiology, immunofluorescent staining, and biotinylation of surface receptors. Silencing of UBXD4 led to a significant reduction of {alpha}3* nAChRs in rat cortical neurons and dPC12 cells. Biochemical and immunofluorescence studies of endogenous UBXD4 showed that the protein is located in both the ER and cis-Golgi compartments. Our investigations also showed that the {alpha}3 subunit is ubiquitinated and that UBXD4 can interfere with its ubiquitination and consequent degradation by the proteasome. Our data suggest that UBXD4 modulates the distribution of {alpha}3* nAChRs between specialized intracellular compartments and the plasma membrane. This effect is achieved by controlling the stability of the {alpha}3 subunit and, consequently, the number of receptors at the cell surface.

Received Oct. 1, 2008; revised April 2, 2009; accepted April 13, 2009.

Correspondence should be addressed to Mariella De Biasi, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030. Email: debiasi{at}bcm.tmc.edu






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