The immunoproteasome has emerged as a critical molecular machine intricately involved in the pathogenesis and progression of a wide spectrum of diseases, spanning cardiovascular disorders, respiratory ailments, neurodegeneration, retinal diseases, tumors, and autoimmune conditions. Unlike the constitutive proteasome, the immunoproteasome contains unique inducible catalytic subunits—β1i (LMP2), β2i (MECL-1), and β5i (LMP7)—endowing it with specialized proteolytic capabilities that adapt immune responses and maintain cellular proteostasis under stress or pathological conditions. Recent advances have illuminated the multifaceted, subunit-specific roles this proteasome variant plays, positioning it as both a guardian and a villain depending on context, with implications that are reshaping therapeutic strategies.
Cardiovascular diseases illustrate the dual nature of immunoproteasome function vividly. In heart failure, characterized by impaired cardiac output and pathological hypertrophy, the immunoproteasome modulates critical signaling pathways through its subunits. For example, the β5i subunit orchestrates autophagic degradation via regulation of ATG5, facilitating the clearance of hypertrophy-associated proteins like IGF1R and gp130. Its activity converges on the attenuation of maladaptive kinase cascades—including AKT, ERK, and mTOR—thereby influencing cardiomyocyte survival and function. Intriguingly, pharmacological inhibition or genetic knockout of β5i ameliorates myocardial hypertrophy in hypertensive models, highlighting its pathogenic facet.
On the molecular front, the immunoproteasome mediates the degradation of AT1R-associated protein (ATRAP), a negative regulator of the renin-angiotensin system, via β5i activity. This degradation escalates angiotensin II receptor signaling, culminating in inflammatory and fibrotic remodeling pathways mediated by MAPK and STAT3 activation. The low molecular weight protein 2 (LMP2) subunit also champions cardiomyocyte adaptive remodeling through p38 MAPK-dependent upregulation, reinforcing the nuanced balance between damage and repair within the myocardium.
In atrial fibrillation (AF), a disease marked by electrical and structural remodeling of the atrium, immunoproteasome dysregulation exacerbates pathological remodeling. The upregulation of β5i and β2i in angiotensin II–induced AF models propels atrial fibrosis and inflammation by degrading ATRAP and activating the NF-κB and TGF-β/Smad axes. Natural compounds like gallic acid and melatonin inhibit immunoproteasome activity, stabilizing ATRAP levels and counteracting atrial remodeling, offering promising therapeutic avenues for rhythm control and tissue protection.
Heart tissue ischemia and reperfusion injury further underscore the immunoproteasome’s complexity. This proteasomal variant fosters cardioprotection by modulating mitochondrial dynamics—a critical determinant of cardiomyocyte fate. Subunits like β2i govern the fusion-fission balance by regulating proteins such as Parkin, Mfn1/2, and Drp1, thereby preserving mitochondrial integrity and function under oxidative stress. Small molecule activators enhance immunoproteasome activity, boosting antioxidant defenses through pathways like Keap1-NRF2, and fine-tuning apoptotic signaling cascades. Notably, immunoproteasome activity during ischemic preconditioning involves LMP2-dependent PTEN degradation, activating prosurvival Akt signaling and fortifying the myocardium against subsequent insults.
In inflammatory cardiac diseases like myocarditis, the immunoproteasome serves a Janus-faced role. It is pivotal in antigen processing and viral clearance, yet its hyperactivation can exacerbate inflammation, worsening tissue injury. Mouse models infected with Coxsackievirus B3 reveal that the absence of β5i exacerbates myocardial damage due to disrupted protein quality control and oxidative stress. Conversely, selective immunoproteasome inhibitors such as ONX-0914 attenuate immune cell infiltration and cytokine production, illustrating therapeutic potential in modulating immune-mediated myocarditis. In autoimmune myocarditis, inhibiting immunoproteasome catalytic subunits shifts T cell phenotypes toward regulatory profiles, mitigating fibrosis and improving cardiac function, thus positioning the proteasome as a target for immunomodulation.
The immunoproteasome’s involvement in atherosclerosis reflects its capacity to influence vascular inflammation and plaque stability. It modulates endothelial cell adhesion molecules like ICAM1 and VCAM1 through the lncRNA-driven upregulation of PSMB9, enhancing monocyte recruitment and lesion progression. Subunits such as LMP7 suppress efferocytosis by impairing apoptotic cell clearance, enlarging necrotic cores and fueling inflammation. Genetic deletion or pharmacological inhibition of these subunits dampens macrophage-driven inflammatory states, shifts macrophage polarization from pro-inflammatory M1 to reparative M2 phenotypes, and retards atherogenesis. These findings position immunoproteasomal components as effective targets to reverse or prevent progressive vascular pathology.
Respiratory diseases, especially chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis, display marked immunoproteasome activation linked to dysfunctional proteostasis. Elevated misfolded protein stress and mitochondrial DNA damage activate pathways such as cGAS/STING, augmenting immunoproteasome expression and antigen presentation. This cascade fosters autoreactive CD8+ T cell expansion and a proinflammatory milieu, driving persistent lung tissue damage and fibrosis. Immunoproteasome-mediated modulation of adaptive immunity thus bridges protein quality control and chronic respiratory inflammation.
Neurodegenerative disorders highlight another dimension of immunoproteasome function, as the central nervous system confronts the accumulation of misfolded proteins and neuroinflammation. In Alzheimer’s disease, the immunoproteasome is upregulated in reactive astrocytes and microglia surrounding amyloid β plaques, influencing cytokine secretion patterns and neurotoxic inflammation. Targeting immunoproteasome subunits with specific inhibitors ameliorates cognitive deficits without affecting amyloid deposition, evidencing neuroprotective potential. Parkinson’s disease models reveal impaired immunoproteasome assembly driven by α-synuclein overexpression, aggravating protein aggregation and neuronal loss. Similarly, Huntington’s disease and ALS exhibit heightened immunoproteasome presence, underscoring its involvement in proteostasis and inflammatory responses within degenerating neurons and glia.
In retinal pathologies, immunoproteasomal activity modulates critical signaling networks governing vascular and neuronal health. The β5i and β2i subunits facilitate the degradation of regulatory proteins such as ATRAP, PTEN, and ATG5, which control inflammatory and autophagic pathways implicated in retinopathy and ischemic injury. By disrupting these homeostatic axes, the immunoproteasome exacerbates vascular permeability, fibrosis, and pathological angiogenesis. Conversely, immunoproteasome depletion delays retinal ganglion cell apoptosis and adjusts neural progenitor cell dynamics, highlighting a complex influence on retinal degeneration and potential developmental processes.
Cancer, with its hallmark of proteotoxic stress and immune evasion, leverages immunoproteasome function to sustain malignant phenotypes. Many tumors, including multiple myeloma, breast, colorectal cancers, and hematologic malignancies, exhibit enhanced immunoproteasome expression induced by IFN-γ secreted from infiltrating lymphocytes. The immunoproteasome regulates oncogenic transcriptional networks, exemplified in acute myeloid leukemia where PSMB8 dependency intersects with chromatin modulators, enabling cell survival and drug resistance. Selective inhibitors targeting β5i demonstrate potent apoptosis induction in chronic lymphocytic leukemia, overcoming resistance mediated by microenvironmental signals such as p38 MAPK. Additionally, the immunoproteasome governs NF-κB signaling by degrading inhibitors like IκBα, thereby facilitating tumor-promoting gene expression and cellular proliferation. Its role in modulating tumor antigen processing further implicates it in immune recognition and evasion, positioning it as a compelling target for integrated cancer therapies.
Autoimmune diseases encompass another realm where immunoproteasome dysregulation acts as a crucial participant. By regulating T cell differentiation, NF-κB pathway activation, and macrophage cytokine release, the immunoproteasome influences systemic autoinflammatory responses and interferonopathies. Inborn errors of immunity attributed to proteasomal defects manifest as persistent type I interferon signaling, underscoring the proteasome’s significance in maintaining immune tolerance. Models of chronic thyroiditis induced by IFN-γ elucidate immunoproteasomal contributions to organ-specific autoimmunity, broadening their therapeutic relevance beyond immune surveillance into controlling inflammatory cascades at the tissue level.
Taken together, the breadth of the immunoproteasome’s influence across diverse pathologies highlights its indispensable role at the intersection of proteostasis, immune modulation, and cell signaling. This specialized proteasome isoform integrates stress responses with antigen presentation, inflammatory regulation, and cell survival mechanisms, which can alternately exacerbate or alleviate disease. Current research efforts aim to unravel subunit-specific functions and their context-dependent outcomes, paving the way for selectively targeted therapeutics. The advent of immunoproteasome inhibitors and modulators holds promise for transforming treatment paradigms across cardiovascular, neurodegenerative, inflammatory, and malignant diseases, emphasizing the immunoproteasome as a dynamic molecular target in precision medicine.
Subject of Research:
The immunoproteasome’s multifaceted roles in disease pathogenesis and therapeutic potential across cardiovascular, respiratory, neurodegenerative, retinal, tumor, and autoimmune diseases.
Article Title:
Current landscape of the immunoproteasome: implications for disease and therapy.
Article References:
Zou, Z., Hao, Y., Tao, Z. et al. Current landscape of the immunoproteasome: implications for disease and therapy. Cell Death Discov. 11, 406 (2025). https://doi.org/10.1038/s41420-025-02698-0
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02698-0
