Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases

Abstract

Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most-if not all-of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation.

Keywords: autoinflammation; proteasomopathies; proteinopathies; proteostasis; ribosomopathies.

Figure 1

Most inflammatory pathways engaged following proteostasis disruption originate from the ER. Proteostasis perturbations are typically caused by proteasome dysfunction and/or excessive protein misfolding, as indicated. (1) Sustained misfolding of secretory proteins results in their accumulation within the ER lumen and generates ER stress, which is sensed by the IRE1, ATF6 and PERK receptors upon dissociation of the chaperone protein Bip. This, in turn, initiates the UPR that comprises the formation of sXBP1, ATF6f as well as a translational arrest, the activation of ATF4 and the formation of SGs following phosphorylation of eIF2α by PERK. Persistent activation of all UPR branches have been reported to trigger sterile inflammation by various mechanisms (for more details, see main text). (2) Misfolding of IL-24 typically results in its subsequent retro-translocation back to the cytosol by the ERAD machinery. In case of proteasome dysfunction, IL-24 misfolded species accumulate in the cytosol and activate PKR to trigger a type I IFN response and inflammation via eIF2α phosphorylation. (3) Proteome imbalance is also sensed by the short-lived ER-membrane resident protein TCF11/Nrf1 whose turnover rate decreases with increased proteasome dysfunction. This results in its proteolytic cleavage by DDI2, thereby giving rise to a transcription factor inducing the expression of proteasome genes to restore protein homeostasis and mitophagy genes that may exacerbate inflammation through persistent glycolysis, as indicated. (4) Proteasome defects also reduce the intracellular pool of free amino acids and result in mTORC1 downregulation. This, in turn, promotes sterile inflammation by increasing mitophagy and blocking lipid synthesis (for more details, see the main text). Amino acid depletion in the cell also activates GCN2 of the integrated stress response (ISR) which facilitates inflammation following eIF2α phosphorylation.

Figure 2

Proteostasis perturbations may arise at any stage of the protein life cycle and typically result in the initiation of sterile inflammation. Depicted are three pathological situations causing impaired proteostasis in which translation (1), protein folding (2) and proteasome-mediated protein degradation of defective ribosomal products (DRiPs) following their polyubiquitination by E1, E2 and E3 enzymes of the ubiquitin-conjugation pathway (3) are affected.

Figure 3

Molecular pathogenesis of ribosomopathies and their potential inflammatory consequences. The failure of mutant ribosomal proteins of the small 40S (RPS) and/or large 60S (RPL) ribosomal subunits to assemble into ribosomes induces the nucleolar stress response leading to p53 stabilization via persistent inactivation of the MDM2 E3 ubiquitin ligase. This, in turn, results in genome instability and subsequent leakage of double-stranded (ds)DNA into the cytosol. Cytoplasmic dsDNA is then sensed by the cyclic GMP-AMP synthase (cGAS) which promotes a type I IFN response via the STING/IRF3 signaling pathway, as indicated. The recruitment of cGAS in the cytosol is itself facilitated by defective and collided ribosomes.

Figure 4

Neuroinflammation caused by impaired proteostasis in ALS involves multiple pathways. Pathogenic variants of superoxide dismutase 1 (SOD1) facilitate the formation of intracellular protein aggregates which themselves promote sterile inflammation by causing persistent activation of the unfolded protein response (UPR) via inhibition of the ER-associated degradation machinery (ERAD), as indicated. In addition, extracellular SOD1 protein aggregates exert their pro-inflammatory effects by binding to phagocyte pattern recognition receptors such as Toll-like receptors (TLR)-2, 4 and 6. Pathogenic mutations within the TAR DNA-binding protein 43 (TDP-43) results in protein aggregation which activates the inflammasome and triggers the release of mitochondrial (mt) DNA. The latter, in turn, initiates a type I IFN response following sensing by the cytosolic cyclic GMP-AMP (cGAS) synthase and subsequent STING activation, as indicated. NLRP3: NOD-like receptor pyrin domain-containing-3; ASC: apoptosis associated speck-like protein containing a CARD; pro-CASP1: pro-caspase 1.