Photic injury promotes cleavage of p75NTR by TACE and nuclear trafficking of the p75 intracellular domain.
The p75 neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily that paradoxically mediates neuronal survival and differentiation or apoptotic cell death. Cleavage of p75NTR by a constitutively active metalloprotease could result in shedding of its extracellular domain (p75ECD) and generation of a pro-apoptotic intracellular domain (p75ICD). In this study, we established that exposure of a transgenic mouse photoreceptor cell line to intense light upregulated the expression of p75NTR and of the disintegrin metalloprotease tumor necrosis factor-converting enzyme (TACE) and resulted in apoptotic cell death. Light damage promoted TACE cleavage of p75NTR resulting in shedding of the soluble p75ECD and nuclear translocation of the p75ICD. Overexpression of TACE and p75NTR-induced p75NTR cleavage and secretion of p75ECD, but not nuclear transport of p75ICD. Light-induced cleavage of p75NTR, nuclear localization of p75ICD, and apoptosis were inhibited by IC-3, a metalloprotease inhibitor. Increased levels of p75NTR and TACE were observed in photoreceptor cells of animals with photic injury. Our findings support a role for TACE in the proteolytic cleavage of p75NTR and light-induced apoptosis.
Srinivasan
Bhooma
B
Department of Cell Biology and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Wang
Zhaohui
Z
Brun-Zinkernagel
Anne M
AM
Collier
Robert J
RJ
Black
Roy A
RA
Frank
Stuart J
SJ
Barker
Philip A
PA
Roque
Rouel S
RS
D051722:ADAM Proteins / Q000378:metabolism* / Q000528:radiation effects; D000072198:ADAM17 Protein; D021581:Active Transport, Cell Nucleus / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects; D007424:Intracellular Fluid / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010775:Photic Stimulation / Q000009:adverse effects*; D010786:Photoreceptor Cells / Q000293:injuries / Q000378:metabolism* / Q000528:radiation effects; D017434:Protein Structure, Tertiary / Q000502:physiology / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism* / Q000528:radiation effects; D012160:Retina / Q000293:injuries / Q000378:metabolism* / Q000528:radiation effects
D020800:Receptor, Nerve Growth Factor; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat