GDP-mannose-4,6-dehydratase is a cytosolic partner of tankyrase 1 that inhibits its poly(ADP-ribose) polymerase activity.
Tankyrase 1 is a poly(ADP-ribose) polymerase (PARP) that participates in a broad range of cellular activities due to interaction with multiple binding partners. Tankyrase 1 recognizes a linear six-amino-acid degenerate motif and, hence, has hundreds of potential target proteins. Binding of partner proteins to tankyrase 1 usually results in their poly(ADP-ribosyl)ation (PARsylation) and can lead to ubiquitylation and proteasomal degradation. However, it is not known how tankyrase 1 PARP activity is regulated. Here we identify GDP-mannose 4,6-dehydratase (GMD) as a binding partner of tankyrase 1. GMD is a cytosolic protein required for the first step of fucose synthesis. We show that GMD is complexed to tankyrase 1 in the cytosol throughout interphase, but its association with tankyrase 1 is reduced upon entry into mitosis, when tankyrase 1 binds to its other partners TRF1 (at telomeres) and NuMA (at spindle poles). In contrast to other binding partners, GMD is not PARsylated by tankyrase 1. Indeed, we show that GMD inhibits tankyrase 1 PARP activity in vitro, dependent on the GMD tankyrase 1 binding motif. In vivo, depletion of GMD led to degradation of tankyrase 1, dependent on the catalytic PARP activity of tankyrase 1. We speculate that association of tankyrase 1 with GMD in the cytosol sequesters tankyrase 1 in an inactive stable form that can be tapped by other target proteins as needed.
Molecular Pathogenesis Program and Department of Pathology, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA.
Kamlesh K
KK
Bisht
Charles
C
Dudognon
William G
WG
Chang
Ethan S
ES
Sokol
Alejandro
A
Ramirez
Susan
S
Smith
D034961:Antigens, Nuclear / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D006836:Hydro-Lyases; D034521:Nuclear Matrix-Associated Proteins; D034741:RNA, Small Interfering; D038501:Tankyrases; D035321:Telomeric Repeat Binding Protein 1; C050045:NUMA1 protein, human; C418109:TNKS protein, human