Immunoproteasomes control activation of innate immune signaling and microglial function

Abstract

Microglia are the resident immune cells of the central nervous system (CNS) and play a major role in the regulation of brain homeostasis. To maintain their cellular protein homeostasis, microglia express standard proteasomes and immunoproteasomes (IP), a proteasome isoform that preserves protein homeostasis also in non-immune cells under challenging conditions. The impact of IP on microglia function in innate immunity of the CNS is however not well described. Here, we establish that IP impairment leads to proteotoxic stress and triggers the unfolded and integrated stress responses in mouse and human microglia models. Using proteomic analysis, we demonstrate that IP deficiency in microglia results in profound alterations of the ubiquitin-modified proteome among which proteins involved in the regulation of stress and immune responses. In line with this, molecular analysis revealed chronic activation of NF-κB signaling in IP-deficient microglia without further stimulus. In addition, we show that IP impairment alters microglial function based on markers for phagocytosis and motility. At the molecular level IP impairment activates interferon signaling promoted by the activation of the cytosolic stress response protein kinase R. The presented data highlight the importance of IP function for the proteostatic potential as well as for precision proteolysis to control stress and immune signaling in microglia function.

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

“…Induction of another immunoproteasome subunit β1i was recently shown to facilitate adaptation to mitochondrial stress and prevent formation of intracellular aggregates ( Kim et al, 2023 ). In β5iKO mice, impaired proteostasis with accumulation of ubiquitinated proteins was revealed in microglia ( Cetin et al, 2022 ). These findings are in line with the role of immunoproteasome in prevention of aggregate formation after stress ( Seifert et al, 2010 ).…”

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

“…While proteasome-mediated suppression of inflammatory/immune responses might be an evolutionarily conserved phenomenon, the exact mechanisms of how immune responses are kept in check are likely to differ. For example, activation of type-I interferon signaling in mammals as a consequence of proteasome dysfunction has been attributed to ER stress and activation of the unfolded protein response (UPR) [ 28 , 50 , 51 ]. This is unlikely to be the case in the context of oomycete recognition as we have previously shown that introducing ER stress does not induce chil-27p :: GFP [ 2 ].…”

Immunoproteasome deficiency results in accelerated brain aging and epilepsy

“…According to the cooperative model for immunoproteasome assembly, LMP7 subunit has a central role, as the lack of this subunit impairs the incorporation of LMP2 and MECL-1 into newly synthetized proteasome complex (Griffin et al, 1998). Recently, mice deficient in LMP7 were shown to have an impairment in proteotoxic stress related to defective microglial function (Cetin et al, 2022). However, only the complete deficiency of all three immunoproteasome subunits results in age-related epileptic seizures, suggesting that mice lacking LMP7 have still a relatively functional ubiquitin-proteasome system.…”