The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization.
Agonist-induced ubiquitination of the beta(2) adrenergic receptor (beta(2)AR) functions as an important post-translational modification to sort internalized receptors to the lysosomes for degradation. We now show that this ubiquitination is reversed by two deubiquitinating enzymes, ubiquitin-specific proteases (USPs) 20 and 33, thus, inhibiting lysosomal trafficking when concomitantly promoting receptor recycling from the late-endosomal compartments as well as resensitization of recycled receptors at the cell surface. Dissociation of constitutively bound endogenously expressed USPs 20 and 33 from the beta(2)AR immediately after agonist stimulation and reassociation on prolonged agonist treatment allows receptors to first become ubiquitinated and then deubiquitinated, thus, providing a 'trip switch' between degradative and recycling pathways at the late-endosomal compartments. Thus, USPs 20 and 33 serve as novel regulators that dictate both post-endocytic sorting as well as the intensity and extent of beta(2)AR signalling from the cell surface.
Berthouze
Magali
M
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Venkataramanan
Vidya
V
Li
Yi
Y
Shenoy
Sudha K
SK
D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D020134:Catalytic Domain; D002417:Cattle; D002451:Cell Compartmentation; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination; D000071557:beta-Arrestins
D058666:Adrenergic beta-2 Receptor Agonists; D019390:Arrestins; D050505:Mutant Proteins; D018343:Receptors, Adrenergic, beta-2; C459591:USP20 protein, human; D000071557:beta-Arrestins; C449799:USP33 protein, human; D043222:Ubiquitin Thiolesterase