Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor.
Recent evidence indicates that the transactivation of estrogen receptor alpha (ERalpha) requires estrogen-dependent receptor ubiquitination and degradation. Here we show that estrogen-unbound (unliganded) ERalpha is also ubiquitinated and degraded through a ubiquitin-proteasome pathway. To investigate this ubiquitin-proteasome pathway, we purified the ubiquitin ligase complex for unliganded ERalpha and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP). CHIP preferentially bound to misfolded ERalpha and ubiquitinated it to induce degradation. Ligand binding to the receptor induced the dissociation of CHIP from ERalpha. In CHIP-/- cells, the degradation of unliganded ERalpha was abrogated; however, estrogen-induced degradation was observed to the same extent as in CHIP+/+ cells. Our findings suggest that ERalpha is regulated by two independent ubiquitin-proteasome pathways, which are switched by ligand binding to ERalpha. One pathway is necessary for the transactivation of the receptor and the other is involved in the quality control of the receptor.
Tateishi
Yukiyo
Y
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
Kawabe
Yoh-ichi
Y
Chiba
Tomoki
T
Murata
Shigeo
S
Ichikawa
Ken
K
Murayama
Akiko
A
Tanaka
Keiji
K
Baba
Tadashi
T
Kato
Shigeaki
S
Yanagisawa
Junn
J
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C494372:Hspa8 protein, mouse; D008024:Ligands; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025801:Ubiquitin; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex