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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,
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