UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase.
ATP-binding cassette (ABC) transporters are involved in the transport of multiple substrates across cellular membranes, including metabolites, proteins, and drugs. Employing a functional fluorochrome export assay, we found that UVB irradiation strongly inhibits the activity of ABC transporters. Specific inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) restored the function of ABC transporters in UVB-irradiated cells, and PARP-1-deficient cells did not undergo UVB-induced membrane transport inhibition. These data suggest that PARP-1 activation is necessary for ABC transporter functional downregulation. The hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG) was also required, since specific PARG inhibitors, which limit the production of ADP-ribose molecules, restored the function of ABC transporters. Furthermore, ADP-ribose molecules potently inhibited the activity of the ABC transporter P-glycoprotein. Hence, poly(ADP-ribose) metabolism appears to play a novel role in the regulation of ABC transporters.
Dumitriu
I E
IE
Department of Internal Medicine III, Institute for Clinical Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Voll
R E
RE
Kolowos
W
W
Gaipl
U S
US
Heyder
P
P
Kalden
J R
JR
Herrmann
M
M
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D000246:Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001693:Biological Transport, Active / Q000528:radiation effects; D002478:Cells, Cultured; D005456:Fluorescent Dyes / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014466:Ultraviolet Rays
D018528:ATP-Binding Cassette Transporters; D005456:Fluorescent Dyes; D047348:Hydrolyzable Tannins; D000246:Adenosine Diphosphate Ribose; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases