Immunoproteasome deficiency alters retinal proteasome’s response to stress

Abstract

Abbreviations used: BCA, bicinchoninic acid; IjB, inhibitor of NFjB; KO, L7, lmp7 )/) ; L7M1, lmp7 )/) mecl-1 )/) ; NFjB, nuclear factor jB; PA, proteasome activator; RPE, retinal pigment epithelium; WT, wild-type. AbstractOur previous work demonstrated that immunoproteasome is up-regulated in the retina and brain in response to injury that does not involve an inflammatory response (J. Neurochem. 2008; 106:158).These results suggest additional non-immune functions for the immunoproteasome in the cellular stress response pathway. The present study further investigates the potential involvement of the immunoproteasome in responding to the chronic stress of aging or oxidant exposure in the retina and cultured retinal pigment epithelial (RPE) cells from knock-out mice missing either one (lmp7 )/) ) or two (lmp7) immunoproteasome subunits. We show that aging and chronic oxidative stress up-regulates immunoproteasome in the retina and RPE from wild-type mice. No up-regulation of LMP2 was observed in retinas or RPE lacking MECL-1 and/or LMP7, suggesting that the full complement of immunoproteasome subunits is required to achieve maximal up-regulation in response to stress. We also show that RPE deficient in immunoproteasome are more susceptible to oxidation-induced cell death, supporting a role for immunoproteasome in protecting from oxidative stress. These results provide key mechanistic insight into novel aspects of proteasome biology and are an important first step in identifying alternative roles for retinal immunoproteasome that are unrelated to its role in the immune response.

Lifespan of mice and primates correlates with immunoproteasome expression

“…jci.org Volume 125 Number 5 May 2015 oxidized proteins. All 3 immunoproteasome-specific subunits are upregulated under acute exposure to oxidative stress in cell culture (16,29), and knockout of PSMB8 produces increased protein oxidation and decreased oxidative stress resistance in laboratory mice (29,30). Our results show that immunoproteasome levels, as measured by PSMB8, are significantly higher in fibroblasts from longer-lived primates than in cells from shorter-lived primates.…”

“…The immunoproteasome has been reported to play an important role both in degradation of oxidized proteins (16,29,30) and in generation of peptides for MHC class I antigen presentation (31,32). We wished to determine whether the increase in immunoproteasome in cells of longer-lived primate species was accompanied by an increase in other aspects of MHC class I antigen presentation.…”

“…In this comparison we included only Old World The cell lines available to us vary somewhat in both passage number and in the age of the donor animal (summarized in Supplemental Table 1). Several groups have reported elevations of immunoproteasome with organismal aging in muscle, retina, and hippocampus tissue derived from mice and rats (29,(38)(39)(40) as well as with continued passage of primary cells in culture (41). To reduce artifacts of this kind, we used cell lines at the lowest practical passage number, with only 1 cell line used at a passage above 20.…”

Molecular alterations in proteasomes of rat liver during aging result in altered proteolytic activities

“…It was shown that proteasomes containing immuno-subunits have a higher capacity to degrade oxidized proteins than standard-proteasomes . Therefore, the age-dependent increment in intermediate-type and immuno-proteasomes might belong to those cellular mechanisms aimed to balance the consequences of the impaired antioxidative capacity in aging liver (Hussong et al 2010;Suh et al 2004;Stio et al 1994). Since an age-related increase in immuno-subunits was also observed in other tissues, e.g., in skeletal muscle (Husom et al 2004) and brain (Gavilan et al 2009;Mishto et al 2006), we suggest that part of the mechanism to keep up proteostasis during aging is the formation of immunoproteasomes (Mishto et al 2003).…”

Characterization of the Interaction between the Matrix Protein of Vesicular Stomatitis Virus and the Immunoproteasome Subunit LMP2

“…The immunoproteasome is generally expressed in very small amounts in all cells, with the exception of cells from the immune system. However, it can be significantly upregulated through factors like gamma interferon or oxidative stress (23,24). In the immunoproteasome, the subunits ␤1, ␤2, and ␤5 are replaced by the catalytic subunits ␤1i (LMP2, PSMB9), ␤2i (MECL-1, PSMB10), and ␤5i (LMP7, PSMB8), respectively (25)(26)(27).…”