Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates.
Nitrogen-containing bisphosphonates are pyrophosphate analogs that have long been the preferred prescription for treating osteoporosis. Although these drugs are considered inhibitors of prenylation and are believed to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation seems to be insufficient. Because other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, we first investigated here the effects of bisphosphonates on simian virus 40 and adenovirus infections and, to our surprise, found that viral infections are suppressed by bisphosphonates through a prenylation-independent pathway. By in-house affinity-capture techniques, dynamin-2 was identified as a new molecular target of bisphosphonates. We present evidence that certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2. Hence, this study has uncovered a previously unknown mechanism of action of bisphosphonates and offers potential novel use for these drugs.
Masaike
Yuka
Y
Integrated Research Institute, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8503, Japan.
Takagi
Takeshi
T
Hirota
Masataka
M
Yamada
Joe
J
Ishihara
Satoru
S
Yung
Tetsu M C
TM
Inoue
Takamasa
T
Sawa
Chika
C
Sagara
Hiroshi
H
Sakamoto
Satoshi
S
Kabe
Yasuaki
Y
Takahashi
Yasuyuki
Y
Yamaguchi
Yuki
Y
Handa
Hiroshi
H
D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D004164:Diphosphonates / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000639:trends; D034285:Dynamin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010024:Osteoporosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D034285:Dynamin II