Isopeptide and ester bond ubiquitination both regulate degradation of the human dopamine receptor 4

The Journal of Biological Chemistry
Jennifer C PeelerThomas P Sakmar

Abstract

How an optimal level of human dopamine D4 receptor (hD4R) is maintained in synaptic membranes is not known. We show here that hD4R is ubiquitinated in primary neurons. We go on to show that ubiquitin is attached to hD4R through isopeptide and ester bonds. When lysine (Lys) residues of the hD4R are substituted with arginine (Arg) residues, cellular hD4R protein levels increase. A synergistic effect on hD4R levels is noted when cytoplasmic serine (Ser) and threonine (Thr) residues are mutated. Chloroquine, an inhibitor of lysosomal degradation, did not have an effect on hD4R protein levels. However, treatment with bortezomib, an inhibitor of the 20S proteasome, caused a dose-dependent increase in hD4R protein levels. The effect of bortezomib was attenuated in the receptor variants that lacked Lys or Ser/Thr residues, and the hD4R mutant that lacked 17 cytoplasmic Lys, Ser, and Thr residues was nearly insensitive to bortezomib treatment. We conclude that both isopeptide and ester bond ubiquitination regulate proteasomal degradation of hD4R.

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Citations

May 8, 2019·International Journal of Molecular Sciences·Fiona LimanaqiFrancesco Fornai
Sep 7, 2019·The Journal of Physiology·Florian I Schmidt
Sep 19, 2020·Nature Chemical Biology·Kaitlin A Chambers, Rebecca A Scheck
Jun 9, 2020·Acta Biochimica Et Biophysica Sinica·Yilin Chen, Jianping Jin
Sep 9, 2020·Clinical and Translational Medicine·Xiaoxuan YuHui Hui
May 17, 2019·Neuroscience and Biobehavioral Reviews·Fiona LimanaqiFrancesco Fornai

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Methods Mentioned

BETA
ubiquitination
proximity ligation assay
immunoprecipitation
two-hybrid
transfections
Protein Assay
transfection

Software Mentioned

Prism
Adobe Photoshop
NIS
Adobe Illustrator

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