Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module.
The SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro, ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo, knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Wenqian
W
Li
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Boyko S
BS
Atanassov
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Xianjiang
X
Lan
School of Biological Sciences, Division of Cell Biology and Biophysics, University of Missouri-Kansas City, Kansas City, Missouri, USA.
Ryan D
RD
Mohan
Stowers Institute for Medical Research, Kansas City, Missouri, USA.
Selene K
SK
Swanson
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Aimee T
AT
Farria
Stowers Institute for Medical Research, Kansas City, Missouri, USA.
Laurence
L
Florens
Stowers Institute for Medical Research, Kansas City, Missouri, USA.|Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
Michael P
MP
Washburn
Stowers Institute for Medical Research, Kansas City, Missouri, USA.
Jerry L
JL
Workman
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA sroth@mdanderson.org.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Sharon Y R
SYR
Dent
D001943:Breast Neoplasms / Q000378:metabolism*; D002465:Cell Movement; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D013869:Thiolester Hydrolases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D015854:Up-Regulation
C527169:ATXN7L3 protein, human; C000620273:ATXN7L3B protein, human; C527171:Eny2 protein, human; D006657:Histones; D014157:Transcription Factors; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human