Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve.
Peripheral sensory neurons respond to axon injury by activating an importin-dependent retrograde signaling mechanism. How is this mechanism regulated? Here, we show that Ran GTPase and its associated effectors RanBP1 and RanGAP regulate the formation of importin signaling complexes in injured axons. A gradient of nuclear RanGTP versus cytoplasmic RanGDP is thought to be fundamental for the organization of eukaryotic cells. Surprisingly, we find RanGTP in sciatic nerve axoplasm, distant from neuronal cell bodies and nuclei, and in association with dynein and importin-alpha. Following injury, localized translation of RanBP1 stimulates RanGTP dissociation from importins and subsequent hydrolysis, thereby allowing binding of newly synthesized importin-beta to importin-alpha and dynein. Perturbation of RanGTP hydrolysis or RanBP1 blockade at axonal injury sites reduces the neuronal conditioning lesion response. Thus, neurons employ localized mechanisms of Ran regulation to control retrograde injury signaling in peripheral nerve.
Yudin
Dmitry
D
Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
Hanz
Shlomit
S
Yoo
Soonmoon
S
Iavnilovitch
Elena
E
Willis
Dianna
D
Gradus
Tal
T
Vuppalanchi
Deepika
D
Segal-Ruder
Yael
Y
Ben-Yaakov
Keren
K
Hieda
Miki
M
Yoneda
Yoshihiro
Y
Twiss
Jeffery L
JL
Fainzilber
Mike
M
D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D028884:Karyopherins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D008297:Male; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012183:Retrograde Degeneration / Q000201:enzymology* / Q000473:pathology; D020426:Sciatic Neuropathy / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D020931:ran GTP-Binding Protein / Q000378:metabolism* / Q000502:physiology
D028884:Karyopherins; D020931:ran GTP-Binding Protein