Biology subjects

Bender, F.

Publications and source records attributed to Bender, F..

5 recordsLinked to original sources

bioRxiv2026

Mechanical stress-induced release of mitochondrial double-stranded RNA activates RIG-I to drive osteogenic differentiation in aortic disease

Background: Gain-of-function mutations in RIG-I and MDA5 (RIG-I-like receptors, RLR) cause Singleton-Merten syndrome, an interferonopathy with early aortic calcification. Here we set out to study a possible involvement of RIG-I-like receptor signaling in the formation of aortic valve stenosis in general. Methods and results: We investigated whether mechanical stress-induced RLR activation promotes osteogenic differentiation and calcification of primary human aortic cells, whether such RLR activation drives the development of aortic valve stenosis in vivo, and whether inhibition of downstream JAK/STAT activation ameliorates aortic valve stenosis. We found that activation of primary human aortic interstitial cells by exogenous RIG-I- and MDA5 agonists induced a type I interferon response and an osteogenic program including increased expression of BMP-2 and BSP2, and promoted calcification. These effects were RIG-I/MDA5 or MAVS-dependent, as assessed by CRISPR/Cas9 knockouts. The stress-granule protein G3BP1 and the Wnt receptor FZD5 were induced downstream of RLR activation and were required for osteogenic gene expression and calcification. To assess a potential endogenous source of RIG-I activation, mechanical stretch mimicking valvular tissue stress was applied in cell cuture, which induced a significant RIG-I-dependent interferon response. Sequencing of highly purified preparations of double-stranded RNA from stretched cells demonstrated a predominant mitochondrial origin of double-stranded RNA, and depleting mitochondrial RNA abolished the stretch-dependent response. The JAK/STAT inhibitor ruxolitinib suppressed the RIG-I-induced response including the expression of osteogenic factors in vitro. In a murine wire-injury model of aortic stenosis, MAVS deficiency attenuated valvular morphological changes and improved hemodynamic parameters. Ruxolitinib attenuated hemodynamic progression, prevented aortic stenosis development, and improved survival. Conclusions: Altogether, our results demonstrate that the mechanical-stress-induced release of mitochondrial double-stranded RNA activates RIG-I signaling in aortic interstitial cells, thereby driving osteogenic differentiation and calcification via a MAVS- and G3BP1-dependent pathway. JAK/STAT inhibition with ruxolitinib mitigates this process in a mouse model of aortic valve stenosis, identifying a candidate therapeutic strategy.

cell biology↗

bioRxiv2026

The actin motor protein MYO10 facilitates post-entry spread of respiratory syncytial virus

Human respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants. However, host factors that influence disease severity remain incompletely defined. While clinical risk factors are known, identifying genetic susceptibility has been challenging. In this study, we combined human genetics with functional virology to identify host factors that modulate RSV infection and spread. Starting from a cohort of infants hospitalized with severe RSV disease, we prioritized rare coding variants present in homozygous form and predicted to cause strong functional impairment, and selected candidate genes for mechanistic follow-up. Functional interrogation of 23 candidates by CRISPR/Cas9 knockout screening in human lung epithelial cells identified unconventional myosin-X (MYO10), encoding the actin-based motor protein myosin-X, as a critical host factor for RSV. Genetic disruption or siRNA-mediated depletion of MYO10 significantly reduced RSV infectivity, with the strongest effects at post-entry stages of the viral life cycle. Loss of MYO10 impaired filopodia formation, cell migration, and wound healing, leading to altered cell-cell connectivity and restricted viral dissemination. MYO10 depletion reduced both short-range cell-to-cell transmission and longer-distance extracellular spread, resulting in fewer infected cells and diminished accumulation of progeny virus in culture supernatants. In contrast, RSV entry, early gene expression, and interferon responses were unaffected. Finally, a rare homozygous MYO10 motor-domain variant (rs7737765; H148Y), enriched in severe cases, also reduced RSV replication in cell culture--opposite to expectations for a risk allele--yet underscoring biological relevance and suggesting that MYO10 variation may influence disease in vivo through additional effects on epithelial function. ImportanceRespiratory syncytial virus (RSV) is a major cause of severe respiratory illness in infants, yet it remains unclear why some children develop more serious disease than others. In this study, we combined patient genetic data with laboratory experiments to identify host factors that influence how RSV spreads in the lung. We found that the human protein MYO10, which mediates the formation of small cell protrusions, plays a key role in enabling the virus to spread from cell to cell. When MYO10 was disrupted, viral spread was strongly reduced, even though early steps of infection were unaffected. Interestingly, a rare genetic variant in MYO10 found in patients also altered viral replication, highlighting potential clinical relevance. These findings provide new insight into how host cell architecture contributes to RSV infection and suggest that targeting host pathways involved in viral spread could complement existing antiviral strategies.

microbiology↗

bioRxiv2026

Synaptic dynamics as a tunable substrate shaping neuronal activity sequences

A central tenet of cerebellar computation posits that granule cells generate sparse spatiotemporal activity patterns that support precisely timed motor and cognitive outputs. Using high-speed in vivo calcium and glutamate imaging combined with slice electrophysiology, we show that heterogeneous synaptic dynamics transform mossy fiber inputs into temporally sparse, sequential patterns of GC activity. Region-specific differences in MF glutamate release shape GC response duration and sparsity, tuning the temporal statistics of population sequences to match sensorimotor associative learning demands. These findings provide direct evidence for temporally sparse GC sequences and establish synaptic dynamics as a ubiquitous, tunable mechanism structuring neural activity in time.

neuroscience↗

bioRxiv2026

Inositol hexakisphosphate Functions as a Cofactor and Modulator of ADAR1 Activity

Adenosine-to-inosine (A-to-I) RNA editing by ADAR1 is a key post-transcriptional modification, and mutations in ADAR1 lead to Aicardi-Goutieres syndrome (AGS), an autoimmune disorder. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Using a combination of biochemical approaches, inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, molecular dynamics simulations, and a cell-permeable inositol hexakisphosphate (IP6) prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. Furthermore, we identify the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly coordinates a Zn{superscript 2}-ion. Finally, we show that the AGS-associated ADAR1 mutation N907S impairs RNA editing activity, most likely by altering the hydrogen-bond interaction network linking IP6 to the ADAR1 catalytic center. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity and highlight cofactor availability and interaction networks as strategies for therapeutically modulating RNA editing.

molecular biology↗

bioRxiv2020

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

The unfolded protein response (UPR) is associated with the hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in UPR. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR, and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2 enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in humans with fatty liver disease, with only males showing an accumulation of CRELD2 protein in the liver. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

molecular biology↗