Biology Reference
In-Depth Information
receptor, but overexpression of USP33 and USP20 counteracts these effects
and promotes receptor recycling and resensitization. 63 Additionally, knock-
down of both USP33 and USP20 abolishes receptor recycling and res-
ensitization, but enhances ubiquitination and lysosomal degradation.
USP20 and USP33 thus act as novel regulators that dictate the postendocytic
fate of internalized b 2 ARs. These DUBs are constitutively bound to the cell-
surface b 2 ARs; however, b 2 AR-USP association decreases upon agonist
activation, while simultaneously agonist stimulation leads to the recruitment
of b -arrestins to the b 2 AR with a resultant increase in b -arrestin-USP33
binding. Thus, isoproterenol stimulation induces a reciprocal pattern of
USP33 interaction with the b 2 AR and b -arrestin2: dissociation of USP33
from the b 2 AR and association of USP33 with b -arrestin2. 63 These data
support the idea that while b -arrestin2 facilitates b 2 AR ubiquitination by
recruiting Nedd4, it might also serve to remove the DUBs from the acti-
vated b 2 AR to facilitate receptor ubiquitination.
Reassociation of the DUBs during b 2 AR trafficking leads to receptor
deubiquitination, preventing lysosomal degradation of the receptors while
concomitantly promoting receptor recycling and resensitization ( Fig. 7.5 ).
Thus, USP20 and 33 function as a tag team to separate internalizing
b 2 AR and b -arrestin, leading to a tight regulation and balancing of signaling
and internalization processes. For the 7TMR protease-activated receptor 2,
lysosomal trafficking has been reported to be regulated by the DUBs AMSH
and UBPY, and the cell-surface trafficking of A2 adenosine receptor
requires USP4-mediated deubiquitination; however, the role of b -arrestin
in these processes is not known. 97,98
6. ARRESTIN-LIKE PROTEINS
Although nonmetazoans do not express a homolog of mammalian
arrestins, proteins that lack sequence homology and yet show structural con-
servation with the arrestin N and C domains have been recently
described. 99,100 Similar arrestin domain-containing proteins also exist in
mammals, and the following sections describe their known functions and
analogy to b -arrestins.
6.1. Aspergillus nidulans
In the model fungus A. nidulans , the arrestin-like protein PalF forms a critical
component of the fungal ambient pH-signaling pathway. 101
Increase in
extracellular pH activates
the 7TMR PalH leading to recruitment,
Search WWH ::




Custom Search