Immunoproteasome is a proteasome sub-type that is known to produce antigenic
peptides for MHC class I presentation. However, immunoproteasome is present in the
immune-privileged brain and retina and is upregulated with disease in human retina and
injury in mouse retina and brain, suggesting functions unrelated to its role in the immune
system. The goal of this thesis is to define novel roles for the immunoproteasome in the
Potential functions of the immunoproteasome were defined by comparing the
stress response of wild-type and knock-out mice missing one (lmp7-/-(L7)) or two (lmp7-/-
/mecl-1-/-(L7M1)) of the three immunoproteasome subunits. Aging was used as a model
system for chronic stress. Chronic peroxide exposure in cultured retinal pigment
epithelial (RPE) cells developed from wild-type mice was used as an additional stress
model. In wild-type retinas and RPE cells, upregulation of immunoproteasome was
observed in response to both models of chronic stress. To determine the consequence of
eliminating immunoproteasome, the retinas and RPE cells from KO mice were examined.L7M1 retina had significantly elevated levels of photoreceptor apoptosis that further
increased with age. In addition, L7M1 cell lines were more susceptible to oxidantinduced
death. Together these data suggest immunoproteasome is protective against
The localization of immunoproteasome to the outer plexiform layer in wild-type
retina suggested a role in retinal function. Electroretinography was used to test the
hypothesis that immunoproteasome is required for maintaining normal visual
transmission. Data indicated that immunoproteasome-deficient mice had a decreased
bipolar cell response as compared to wild-type. Evaluation of several retinal synapse proteins by Western blot revealed no significant difference in protein content across
strains. In addition, gross retinal morphology and bipolar cell density were not different.
In conclusion, immunoproteasome-deficiency causes a decrease in visual transmission
but the mechanism is still unclear.
In summary, these data provide compelling evidence that immunoproteasome has
a role in retinal stress response, specifically in protecting against oxidative stress. Furthermore, immunoproteasome-deficient mice have a decreased bipolar cell response
as measured by ERG. Altogether, data from this thesis strongly support the hypothesis
that immunoproteasome has additional functions in the retina that do not involve immune
University of Minnesota Ph.D. dissertation. October 2010. Major: Biochemistry, Molecular Bio, and Biophysics. Advisors: Dr. Deborah A. Ferrington, Ph.D., 1 computer file (PDF); xii, 204 pages, appendix p. 200-204.
Hussong, Stacy Ann.
Identifying novel roles for the immunoproteasome in the retina..
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