On the Role of the Immunoproteasome in Protein Homeostasis

Basler, Michael; Groettrup, Marcus

doi:10.3390/cells10113216

Cited by 26 publications

(19 citation statements)

References 116 publications

(189 reference statements)

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“…Antioxidant treatment prevents IP translocation into mitochondria, suggesting IP involvement in mitochondrial quality control [ 54 ]. A recent study showed that mitochondrial dysfunction in aged mouse lungs determined downregulation of oxidative phosphorylation and, on the contrary, a significant increase in immune response pathways dependent on IP function [ 58 ]. In line with these findings, we observed relevant modifications at the metabolic level following ONX-0914 administration, as indicated by the upregulation of SDH+ fibers and modulation of myofiber type frequency and distribution.…”

Section: Discussionmentioning

confidence: 99%

Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment

Tripodi

Molinaro

Fortunato

et al. 2022

IJMS

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Muscle wasting is a major pathological feature observed in Duchenne muscular dystrophy (DMD) and is the result of the concerted effects of inflammation, oxidative stress and cell senescence. The inducible form of proteasome, or immunoproteasome (IP), is involved in all the above mentioned processes, regulating antigen presentation, cytokine production and immune cell response. IP inhibition has been previously shown to dampen the altered molecular, histological and functional features of 3-month-old mdx mice, the animal model for DMD. In this study, we described the role of ONX-0914, a selective inhibitor of the PSMB8 subunit of immunoproteasome, in ameliorating the pathological traits that could promote muscle wasting progression in older, 9-month-old mdx mice. ONX-0914 reduces the number of macrophages and effector memory T cells in muscle and spleen, while increasing the number of regulatory T cells. It modulates inflammatory markers both in skeletal and cardiac muscle, possibly counteracting heart remodeling and hypertrophy. Moreover, it buffers oxidative stress by improving mitochondrial efficiency. These changes ultimately lead to a marked decrease of fibrosis and, potentially, to more controlled myofiber degeneration/regeneration cycles. Therefore, ONX-0914 is a promising molecule that may slow down muscle mass loss, with relatively low side effects, in dystrophic patients with moderate to advanced disease.

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Section: Discussionmentioning

confidence: 99%

Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment

Tripodi

Molinaro

Fortunato

et al. 2022

IJMS

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“…Nevertheless, we hypothesized that LMP7 upregulates A20 in airway epithelial cells as a protective mechanism against RV-induced inflammation. IP has been reported to have function in protein homeostasis by preventing accumulation of damaged proteins 39 . During RV infection, viral replication enhanced the production of misfolded and damaged proteins leading to IP induction for efficient degradation.…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection

Dimasuay

Schaunaman

Berg

et al. 2022

Sci Rep

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Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear. In this study, we determined whether airway epithelial LMP7 promotes the resolution of RV-mediated lung inflammation. Inducible airway epithelial-specific LMP7-deficient (conditional knockout, CKO) mice were generated to reveal the in vivo anti-inflammatory and antiviral functions of LMP7. By using LMP7-deficient primary human airway epithelial cells generated by CRISPR-Cas9, we confirmed that airway epithelial LMP7 decreased pro-inflammatory cytokines and viral load during RV infection. Additionally, airway epithelial LMP7 enhanced the expression of a negative immune regulator A20/TNFAIP3 during viral infection that may contribute to the anti-inflammatory function of LMP7. We also discovered that induction of LMP7 by a low dose of polyinosinic:polycytidylic acid (PI:C) reduced RV-mediated inflammation in our CKO mice infected with RV. Our findings suggest that airway epithelial LMP7 has anti-inflammatory and antiviral functions that is critical to the resolution of RV-mediated lung inflammation. Induction of airway epithelial LMP7 may open a novel avenue for therapeutic intervention against RV infection.

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“…Proteostasis regulation and proteome integrity are essential for physiological cellular function. The proteasomes are multisubunit protease complexes that selectively catalyze the degradation of short-lived regulatory proteins and damaged peptides may directly affect the substrate selectivity regulating proteostasis maintenance in response to certain intracellular and extracellular conditions [104,105]. Thus, the proteasome contributes to controlling key processes that affect the cellular state, such as adaptation to environmental cues, growth, development, metabolism, signaling, senescence, pluripotency, differentiation, and immunity.…”

Section: Proteostasismentioning

confidence: 99%

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis

Terracina

Ferraguti

Petrella

et al. 2023

CCDT

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Evidence shows that there is a synergistic, bidirectional association between cancer and aging with many shared traits. Age itself is a risk factor for the onset of most cancers while evidence suggests that cancer and its treatments might accelerate aging by causing genotoxic and cytotoxic insults. Aging has been associated with a series of alterations that can be linked to cancer: i) genomic instability caused by DNA damage or epigenetic alterations coupled with repair errors, which lead to progressive accumulation of mutations; ii) telomere attrition with possible impairment of telomerase, shelterin complex, or the trimeric complex (Cdc13, Stn1 and Ten1 – CST) activities associated with abnormalities in DNA replication and repair; iii) altered proteostasis especially when leading to an augmented proteasome, chaperon and autophagy-lysosome activity; iv) mitochondrial dysfunction causing oxidative stress; v) cellular senescence; vi) stem cells exhaustion, intercellular altered communication and deregulated nutrient sensing which are associated with microenvironmental modifications which may facilitate the subsequential role of cancer stem cells. Nowadays anti-growth factor agents and epigenetic therapies seem to assume an increasing role to fight aging-related diseases, especially cancer. This report aims to discuss the impact of age on cancer growth.

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On the Role of the Immunoproteasome in Protein Homeostasis

Cited by 26 publications

References 116 publications

Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment

Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment

Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis

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