Acetylation modulates prolactin receptor dimerization.
Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling pathways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5, which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation.
Departments of Surgery and Medicine, Brown University School of Medicine-Rhode Island Hospital, Providence, RI 02903, USA.
Li
L
Ma
Jin-song
JS
Gao
Yingjie
Y
Guan
Xiaoyan
X
Shi
Hao
H
Zhang
Marina K
MK
Ayrapetov
Zhe
Z
Zhang
Li
L
Xu
Young-Min
YM
Hyun
Minsoo
M
Kim
Shougang
S
Zhuang
Y Eugene
YE
Chin
D000107:Acetylation; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008239:Lysine / Q000378:metabolism; D055503:Protein Multimerization; D011981:Receptors, Prolactin / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism
D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D050882:CREB-Binding Protein; D008239:Lysine