bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.08.29.672721

Atypical p38 Kinase Signaling in Retinal Vascular Damage and Recovery

Schulz, L.·Young, A. E.·Liu, F.·Gattineni, S.·Ghosh, S. S.·Douglass, E.·Kroeger, H.·Narayanan, P.·Grimsey, N. J.
View original source ↗Export metadata ↓

Abstract

Despite the life-changing impact of anti-VEGF therapies, vascular retinopathies continue to affect millions of patients worldwide. To better understand disease progression, it is essential to define alternative mechanisms that contribute to retinal vascular dysregulation. Mitogen-activated protein kinase (MAPK) p38 plays a significant role in regulating vascular homeostasis, angiogenesis, and retinal disease progression, yet effective therapeutic targeting remains elusive. An alternative atypical p38 signaling pathway is mediated by interaction with the adaptor protein TGF-beta activated kinase 1, binding protein 1 (TAB1). Atypical p38 can be activated by ischemia or by inflammatory G protein-coupled receptors (GPCRs) to regulate inflammation and vascular homeostasis. However, atypical signaling has not been investigated in the context of vascular retinopathies, specifically oxygen-induced retinopathy (OIR). Here, we utilized a genetic knock-in mouse to block atypical p38 activity (Tab1KI) to explore retinal damage during OIR. We report that Tab1KI mice display significantly reduced vaso-obliteration and limited neovascularization relative to wild-type C57BL6 controls. Retinal RNAseq analysis revealed distinct transcriptional regulation in the Tab1KI mouse. Suppression of atypical p38 reduced Mef2c signaling, which in turn enhanced microglial activation and inflammation. Despite the upregulation of proangiogenic markers, the increase in endothelial markers does not correlate with the dysregulated growth of blood vessels. Instead, Mef2c suppression reduces pathological angiogenesis, while increasing physiological vascular regrowth. The combined data suggest that the selective inhibition of atypical p38 signaling could block the enhanced pathogenic neovascular tuft formation without impacting blood vessel repair. Further investigation will clarify how atypical p38 controls neovascular responses, potentially revealing new treatment strategies for vascular retinopathies. NEW AND NOTEWORTHYMAPK p38 drives ocular injury and inflammation, but the contribution of Tab1-dependent atypical p38 in retinal injury has not been investigated. Using a mouse genetic knock-in model to block atypical p38 during oxygen-induced retinal injury, we show that atypical p38 enhances vascular damage and neovascular tufting. Blockade of atypical p38 protects mice from retinal vascular damage.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Schulz, L., Young, A. E., Liu, F., Gattineni, S., Ghosh, S. S., Douglass, E., Kroeger, H., Narayanan, P., Grimsey, N. J.. 2025-08-31. Atypical p38 Kinase Signaling in Retinal Vascular Damage and Recovery. https://doi.org/10.1101/2025.08.29.672721

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

KEEP EXPLORING

Related preprints

bioRxiv2026

OPN3 mediates retinal-dependent lipofuscin accumulation and its loss sensitizes keratinocytes to blue-light-induced proteomic remodeling

Lipofuscin is a blue-light-absorbing pigment that contributes to oxidative damage. Whether all-trans retinal (atRAL) contributes to its formation in response to light remains unclear. We asked whether blue-light photosensitization of atRAL promotes lipofuscin accumulation in human keratinocytes and whether this depends on Opsin 3 (OPN3). Blue-light excitation of atRAL reduced mitochondrial and lysosomal viability, impaired autophagic flux, and increased lipofuscin. OPN3 knockdown significantly reduced this accumulation. Label-free data-independent acquisition (DIA) proteomics showed that OPN3 acts at three levels. In the dark, OPN3 loss altered proteome networks associated with autophagy, apoptosis, and interferon-related responses. Under blue light, control cells activated a stress-adaptive program spanning inflammatory regulation, lipid metabolism, and mitochondrial function, which atRAL strongly amplified. This molecular signature, including induction of cellular respiration and ATP-production proteins, was largely absent when OPN3 was silenced. Respirometry showed that blue light suppressed oxygen consumption in both lines over the first 24 h, but a faster recovery in OPN3 knockdown cells at 48 and 72 h was observed. Together, these data define three functions of OPN3: maintaining the basal proteome in a blue-light-independent manner, enabling the adaptive blue-light response, and enabling retinal-dependent lipofuscin formation in keratinocytes.

cell biology↗
bioRxiv2026

Uncoupling microtubule lifetime, stability and post-translational modifications.

Microtubules (MTs) undergo continuous cycles of growth and disassembly. Because the transitions between these states are stochastic, MT age varies widely within a population. As MTs age, they are thought to accumulate post-translational modifications (PTMs) that, directly or indirectly, enhance their stability and thereby extend their lifetime. The rare MTs that withstand prolonged exposure to destabilizing drugs such as nocodazole (NZ) are indeed enriched in PTMs; yet the relationships between MT age, PTMs and stability remain unclear. Using microinjection of labelled tubulin, we measured microtubule network turnover in immortalized mouse embryonic fibroblasts. Half of the network was renewed within 3 minutes and 80% within 10 minutes, while approximately 5% of microtubules persisted for more than 20 minutes. These dynamics were comparable in quiescent and senescent cells, although the fraction of slowly renewing or non-renewing microtubules rose to 20% in senescent cells. Unexpectedly, neither the amount of PTMs (acetylation and detyrosination) nor resistance to NZ increased with MT age, and resistance to NZ was independent of these PTMs. Degrees of acetylation and detyrosination should therefore not be taken as readouts of MT age or stability. Because these PTMs do not accumulate on MTs over time, the chemical modification of polymerized tubulin is likely more reversible and dynamic than previously assumed.

cell biology↗
bioRxiv2026

Evidence of complete myofibril remodeling after severe damage in adult Drosophila.

Muscle function depends on the ability of myofibrils to withstand and repair mechanical damage, yet how adult muscles remodel damaged myofibrils remains poorly understood. Here, we establish a Drosophila model that allows the induction and longitudinal visualization of extensive myofibril damage and recovery in intact adult femur muscles. Sustained muscle depolarization caused extensive disruption of myofibrillar organization, with severe damage characterized by near-complete loss of Z-disc structures. Remarkably, myofibril architecture and muscle function were largely restored within days, revealing a substantial capacity for myofibril reconstruction in adult femur muscles. We identified two distinct states of myofibril damage, mild and severe, with mild damage appearing before severe damage during aging, suggesting a progressive process of myofibril deterioration and repair failure. We further show that filamins mechanosignaling is required for efficient myofibril remodeling. Following damage, wild-type filamin redistributes from the Z-disc and accumulates outside the myofibrils, whereas constitutively open filamin remains Z-disc-associated and constitutively closed filamin redistributes but results in increased damage and impaired recovery. These findings suggest that effective repair requires dynamic transitions between filamin conformational states and that filamin redistribution is an active component of the damage response rather than simply a consequence of muscle injury. During aging, filamin progressively redistributes from the Z-disc and muscle damage accumulates, with severe damage increasing after the appearance of mild damage. Together, our findings reveal a previously unappreciated capacity of adult muscle to reassemble damaged myofibrils and identify filamin mechanosignaling as a key component of this repair process, providing a framework for understanding how defective mechanosensing may contribute to age-related muscle decline and muscle disease.

cell biology↗