Immunoproteasome deficiency protects in the retina after optic nerve crush

Nathan J. Schuld, Stacy A. Hussong, Rebecca J. Kapphahn, Ute Lehmann, Heidi Roehrich, Abrar A. Rageh, Neal D. Heuss, Wendy Bratten, Dale S. Gregerson, Deborah A. Ferrington

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0126768
JournalPloS one
Volume10
Issue number5
DOIs
StatePublished - May 15 2015

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Nerve Crush
Optic Nerve
optics
retina
Retina
Optics
nerve tissue
Retinal Pigments
mice
epithelial cells
Epithelial Cells
pigments
antigen presentation
Wounds and Injuries
Antigen Presentation
protein subunits
Knockout Mice
growth factors
cell viability
Catalytic Domain

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Immunoproteasome deficiency protects in the retina after optic nerve crush. / Schuld, Nathan J.; Hussong, Stacy A.; Kapphahn, Rebecca J.; Lehmann, Ute; Roehrich, Heidi; Rageh, Abrar A.; Heuss, Neal D.; Bratten, Wendy; Gregerson, Dale S.; Ferrington, Deborah A.

In: PloS one, Vol. 10, No. 5, e0126768, 15.05.2015.

Research output: Contribution to journalArticle

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