title: Immunoproteasome deficiency protects in the retina after optic nerve crush.
abstract: The immunoproteasome is upregulated by disease, oxidative stress, and inflammatory cytokines, suggesting an expanded role for the immunoproteasome in stress signaling that goes beyond its canonical role in generating peptides for antigen presentation. The signaling pathways that are regulated by the immunoproteasome remain elusive. However, previous studies suggest a role for the immunoproteasome in the regulation of PTEN and NF-κB signaling. One well-known pathway upstream of NF-κB and downstream of PTEN is the Akt signaling pathway, which is responsible for mediating cellular survival and is modulated after optic nerve crush (ONC). This study investigated the role of retinal immunoproteasome after injury induced by ONC, focusing on the Akt cell survival pathway. Retinas or retinal pigment epithelial (RPE) cells from wild type (WT) and knockout (KO) mice lacking either one (LMP2) or two (LMP7 and MECL-1) catalytic subunits of the immunoproteasome were utilized in this study. We show that mRNA and protein levels of the immunoproteasome subunits are significantly upregulated in WT retinas following ONC. Mice lacking the immunoproteasome subunits show either a delayed or dampened apoptotic response as well as altered Akt signaling, compared to WT mice after ONC. Treatment of the RPE cells with insulin growth factor-1 (IGF-1) to stimulate Akt signaling confirmed that the immunoproteasome modulates this pathway, and most likely modulates parallel pathways as well. This study links the inducible expression of the immunoproteasome following retinal injury to Akt signaling, which is important in many disease pathways.
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Schuld
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America; Graduate Program in Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Hussong
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Kapphahn
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America; Graduate Program in Microbiology, Immunology and Cancer Biology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Ute
authors.initials: U
authors.lastname: Lehmann
authors.affiliation: Histology Core for Vision Research, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Roehrich
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Abrar A
authors.initials: AA
authors.lastname: Rageh
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Heuss
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bratten
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Dale S
authors.initials: DS
authors.lastname: Gregerson
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ferrington
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009409:Nerve Crush / Q000379:methods; D009900:Optic Nerve / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016328:NF-kappa B; C071313:LMP-2 protein; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse