Immunoproteasome Upregulation Is Not Required to Control Protein Homeostasis during Viral Infection

Abstract

The prime function of proteasomes is the control of protein homeostasis in cells (i.e., the removal of proteins that are not properly folded, damaged by stress conditions like reactive oxygen species formation, or degraded on the basis of regular protein turnover). During viral infection, the standard proteasome is replaced by the so-called immunoproteasome (IP) in an IFN-γ–dependent manner. It has been proposed that the IP is required to protect cell viability under conditions of IFN-induced oxidative stress. In this study, we investigated the requirement for IP to cope with the enhanced need for protein degradation during lymphocytic choriomeningitis virus (LCMV) infection in mice lacking the IP subunit LMP7. We found that IP are upregulated in the liver but not in the spleen during LCMV infection, although the total proteasome content was not altered. The expression of standard proteasome subunits is not induced in LMP7-deficient mice, indicating that enhanced proteasomal activity is not required during viral infection. Furthermore, ubiquitin accumulation, apoptosis induction, and viral titers were similar in LCMV-infected mice lacking LMP7 compared with wild-type mice. Taken together, these data indicate that the IP is not required to regulate protein homeostasis during LCMV infection.

On the Role of the Immunoproteasome in Protein Homeostasis

“…Hence, under non-inflammatory conditions, standard proteasomes seem to handle protein degradation without support of immunoproteasomes. This could be confirmed in splenocytes derived from LMP7-deficient mice in a recent study from our laboratory [62]. Additionally, activated B cells derived from LMP2-deficient mice vs. wild-type mice have no significant difference in the levels of poly-ubiquitylated proteins [63].…”

“…The non-cytopathic arenavirus LCMV induces a strong cytotoxic T cell response, which is essential for the elimination of the virus from infected mice. LCMV infection induces a strong up-regulation of immunoproteasomes in the liver on day 8 post infection, an organ that, in naïve state, barely expresses immunoproteasomes [62,73]. In contrast, in the spleen, an organ which contains mainly immunoproteasomes in naïve mice, the immunoproteasome is not induced [62].…”

“…After infection of mice with virus [62,73], fungi [74], or bacteria [75], standard proteasomes are rapidly replaced in infected organs by newly formed immunoproteasomes. The up-regulation of immunoproteasomes has mainly been associated with improved generation of ligands for MHC-I antigen presentation.…”

“…Indeed, activation of T cells leads to a strong increase in the rate of protein synthesis [76,77]. Using virus-specific T cells it was shown that viral infection in mice led to an accumulation of poly-ubiquitylated proteins in CD8 + T cells, 24 h post infection [62]. This indicates that the increase in translation rate in activated T cells results, at least transiently, in an enhanced proteolytic demand.…”

“…However, the total proteasome amount in the liver and spleen is not increased. In that study, it was further investigated whether the immunoproteasome is critically required to cope with the altered challenges in protein degradation during a viral infection [62]. For this, the well-studied lymphocytic choriomeningitis virus (LCMV) was used.…”