Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D.
Calcineurin is a widely expressed and highly conserved Ser/Thr phosphatase. Calcineurin is inhibited by the immunosuppressant drug cyclosporine A (CsA) or tacrolimus (FK506). The critical role of CsA/FK506 as an immunosuppressant following transplantation surgery provides a strong incentive to understand the phosphatase calcineurin. Here we uncover a novel regulatory pathway for cyclic AMP (cAMP) signaling by the phosphatase calcineurin which is also evolutionarily conserved in Caenorhabditis elegans. We found that calcineurin binds directly to and inhibits the proteosomal degradation of cAMP-hydrolyzing phosphodiesterase 4D (PDE4D). We show that ubiquitin conjugation and proteosomal degradation of PDE4D are controlled by a cullin 1-containing E(3) ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3beta (GSK3beta) in a phosphodegron motif. Our findings identify a novel signaling process governing G-protein-coupled cAMP signal transduction-opposing actions of the phosphatase calcineurin and the CK1/GSK3beta protein kinases on the phosphodegron-dependent degradation of PDE4D. This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients.
Zhu
Hong
H
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Suk
Hee Yun
HY
Yu
Raymond Y L
RY
Brancho
Deborah
D
Olabisi
Opeyemi
O
Yang
Teddy T C
TT
Yang
XiaoYong
X
Zhang
Jialin
J
Moussaif
Mustapha
M
Durand
Jorge L
JL
Jelicks
Linda A
LA
Kim
Ja-Young
JY
Scherer
Philipp E
PE
Frank
Philippe G
PG
Lisanti
Michael P
MP
Calvert
John W
JW
Duranski
Mark R
MR
Lefer
David J
DJ
Huston
Elaine
E
Baillie
George S
GS
Houslay
Miles D
MD
Molkentin
Jeffrey D
JD
Jin
Jianping
J
Chow
Chi-Wing
CW
D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D025801:Ubiquitin; D016572:Cyclosporine; D000242:Cyclic AMP; D019703:Calcineurin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D046988:Proteasome Endopeptidase Complex