Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

Kalailingam, P.; Mohd-Kahliab, K.-H.; SoFong Cam Ngan, S. C. N.; Iyappan, R.; Lee, B. S. T.; Bhargy Sharma, B. S.; Machan, R.; Bo, S. T.; Chambers, E. S.; Fajardo, V. A.; Macpherson, R. E. K.; Liu, J.; Klentrou, P.; Tsiani, E. L.; Lim, K. L.; Su, I. H.; Gao, Y.-G.; Richard, A. M.; Kalaria, R. N.; Chen, C. P.; McCarthy, N. E.; Sze, S. K.

doi:10.1101/2023.08.11.552994

Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.08.11.552994

Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

View original source ↗Export metadata ↓

Abstract

Advancing age is the primary risk factor for pulmonary diseases. Our investigation revealed an 8-fold increase in aging induced isoDGR-damaged proteins in lung tissue from human pulmonary fibrosis patients compared to healthy tissues, accompanied by elevated frequencies of CD68+/CD11b+ macrophages, indicating lung tissue is susceptible to time-dependent accumulation of isoDGR-proteins. To elucidate the mechanisms through which isoDGR-proteins may exacerbate aging lung disorders for potential therapeutic targeting, we assessed the functional role of this isoDGR-motif in naturally-aged mice and mice lacking the corresponding isoDGR repair enzyme (Pcmt1-/-). IsoDGR-protein accumulation in mouse lung tissue and blood vessels correlated with chronic low-grade inflammation, pulmonary edema, and hypoxemia. IsoDGR accretion induced mitochondrial and ribosomal dysfunctions, cellular senescence, and apoptosis, contributing to progressive lung damage over time. Treatment with anti-isoDGR antibodies suppressed TLR pathway activity, mitigated cytokine-driven inflammation, restored mtDNA expression, and significantly reduced lung pathology in-vivo. Similarly, exposure of lung endothelial cells to isoDGR-modified fibronectin impaired oxygen consumption, increased reactive oxygen species levels, and disrupted acidification, but these effects were efficiently reversed by target-specific antibody therapy. Collectively, our findings underscore the significant contribution of isoDGR-damaged proteins to age-linked lung pathology. IsoDGR-specific therapy emerges as a promising treatment approach for pulmonary disorders in older patients.

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Kalailingam, P., Mohd-Kahliab, K.-H., SoFong Cam Ngan, S. C. N., Iyappan, R., Lee, B. S. T., Bhargy Sharma, B. S., Machan, R., Bo, S. T., Chambers, E. S., Fajardo, V. A., Macpherson, R. E. K., Liu, J., Klentrou, P., Tsiani, E. L., Lim, K. L., Su, I. H., Gao, Y.-G., Richard, A. M., Kalaria, R. N., Chen, C. P., McCarthy, N. E., Sze, S. K.. 2023-08-14. Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage. https://doi.org/10.1101/2023.08.11.552994

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2025

SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signaling

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.

pathology↗

bioRxiv2025

Germination-stage transcriptomics of the grapevine rust fungus Neophysopella tropicalis reveals protein effectors with plant immunity-suppressing activity

Germination of urediniospores represents a critical early stage in the life cycle of Neophysopella tropicalis, the causal agent of Asian grapevine leaf rust in Brazil. Rust fungi deploy diverse effector proteins to manipulate host immunity and establish infection. This study identified and functionally characterized secreted proteins expressed during early fungal development using RNA-seq analysis of in-vitro-germinated urediniospores. Effectorome analysis revealed 386 putative secreted proteins with hallmarks of fungal effectors, designated as N. tropicalis effector candidates (NtECs). Fifteen highly expressed NtECs were selected for expression profiling by RT-qPCR across infection stages. Fluorescence microscopy with WGA-FITC staining defined key phases of pathogenesis. Although identified during germination, seven NtECs showed elevated transcript accumulation during the penetration and early biotrophic phases, suggesting roles in host entry and establishment. To evaluate immune-suppressing activity, nine NtECs were delivered into Nicotiana benthamiana using the Type III Secretion System of Pseudomonas fluorescens EtHAn. Three effectors (NtEC-05, -09, and -10) strongly suppressed AvrB-triggered cell death, and three others (NtEC-11, -12, and -13) showed moderate suppression. This work provides the first characterization of N. tropicalis effectors, offering insights into rust pathogenesis and supporting future effector-informed strategies for grapevine resistance. HighlightThe grapevine rust fungus Neophysopella tropicalis deploys effectors whose expression aligns with early infection and immune suppression, revealing key virulence mechanisms and guiding effector-informed strategies for grapevine rust resistance.

pathology↗