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JosD1, a membrane-targeted deubiquitinating enzyme, is activated by
ubiquitination and regulates membrane dynamics, cell motility, and endocytosis
#MMPMID23625928
Seki T
; Gong L
; Williams AJ
; Sakai N
; Todi SV
; Paulson HL
J Biol Chem
2013[Jun]; 288
(24
): 17145-55
PMID23625928
show ga
The functional diversity of deubiquitinating enzymes (DUBs) is not well
understood. The MJD family of DUBs consists of four cysteine proteases that share
a catalytic "Josephin" domain. The family is named after the DUB ATXN3, which
causes the neurodegenerative disease Machado-Joseph disease. The two closely
related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more
than the Josephin domain. To gain insight into the properties of Josephin
domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ
fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains.
In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a
form of posttranslational-dependent regulation shared with ATXN3. A significant
fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based
studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes
to the plasma membrane, particularly when ubiquitinated. The membrane occupancy
by JosD1 suggests that it could participate in membrane-dependent events such as
cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1
enhances membrane dynamics and cell motility. JosD1 also influences endocytosis
in cultured cells by increasing the uptake of endocytic markers of
macropinocytosis while decreasing those for clathrin- and caveolae-mediated
endocytosis. Our results establish that two closely related DUBs differ markedly
in activity and function and that JosD1, a membrane-associated DUB whose activity
is regulated by ubiquitination, helps regulate membrane dynamics, cell motility,
and endocytosis.
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