Biology subjects

Tyanova, S.

Publications and source records attributed to Tyanova, S..

5 recordsLinked to original sources

bioRxiv2026

ARMC1 regulates mitochondrial fatty acid oxidation through theinsertase/scramblase MTCH2

MTCH2 (mitochondrial carrier homolog 2) is a noncanonical member of the solute carrier family with five transmembrane (TM) helices, localized to the mitochondrial outer membrane. MTCH2's atypical topology creates a membrane-accessible hydrophilic groove, predicted to be necessary for its protein insertase and lipid scramblase activities. MTCH2 is linked to lipid metabolism and obesity and is required for starvation-induced mitochondrial hyperfusion. Here, we show that MTCH2 is a stable component of a complex containing the Armadillo (ARM) repeat-containing protein, ARMC1, and the DnaJ/Hsp40 chaperone protein, DNAJC11. Protein crosslinking, protein structural modeling, and molecular dynamics simulations demonstrate that the ARMC1 alpha-helical C-terminal domain (CTD) inserts into and stably interacts with the MTCH2 hydrophilic groove and blocks its lipid scramblase activity. We observe that starvation-induced mitochondrial fatty acid oxidation (FAO) is negatively regulated by the ARMC1-MTCH2 interaction. In ARMC1-deficient cells, FAO is stimulated compared to wild-type cells and lipid droplet abundance is significantly reduced. The altered lipid phenotype of ARMC1-/- cells is strictly dependent on MTCH2 and is reversed by ARMC1 expression in a manner dependent on its CTD. Beyond this metabolic axis, we also identify a function for ARMC1 in regulating lysosomal distribution and autophagic flux that is independent of its CTD and interaction with MTCH2. Thus, our data support a model in which the MTCH2-ARMC1 interaction functions as a metabolic switch during starvation to regulate the balance between fat storage and fat burning.

cell biology↗

bioRxiv2026

IRE1 drives a homeostatic response to reduced protein influx into the endoplasmic reticulum

IRE1, alongside ATF6 and PERK, orchestrates the Unfolded Protein Response, a network of signaling pathways that maintains endoplasmic reticulum (ER) homeostasis. Two modes of IRE1 activation are known: i) in response to an accumulation of unfolded proteins in the ER lumen and ii) in response to compositional changes to the ER membrane that alter its physical properties. Here we identify a third, independent mode of IRE1 activation: ER co-translational translocation deficits activate IRE1 through a mechanism that relies on the release of IRE1 molecules from unoccupied translocons. We define this mechanism as TRES for "TRanslocon Engagement Surveillance". TRES leads to spontaneous activation of IRE1 and bypasses its unfolded protein- and ER membrane composition-sensing functions. Inhibiting translation initiation similarly activates IRE1 by TRES, as it leads to a decline in ER protein import, thus linking the Integrated Stress Response to IRE1 signaling. TRES drives IRE1 activation without activating ATF6 or PERK, resulting in a distinct gene expression program that feeds back by boosting the co-translational translocation machinery to rebalance the ER protein load. Our findings thus demonstrate that monitoring and adjusting the rates of protein translocation are critical for maintaining ER homeostasis.

cell biology↗

bioRxiv2025

Intrinsic Molecular Timers and a Biphasic Amplitude Limit Regulate the Integrated Stress Response

The Integrated Stress Response (ISR) is an evolutionarily conserved signaling network that remodels the translatome and transcriptome in response to multiple stresses, including nutrient deprivation, mitochondrial dysfunction, viral infection, and loss of protein homeostasis. Here, we present a comprehensive theoretical model of the ISR, calibrated to time-resolved proteomics data that captures how cells encode the magnitude and duration of stress signals to generate a homeostatic output. Our simulations and data converge on an ISR activation threshold defined by phosphorylated eIF2 levels, and sequential cascading delays in the accumulation of the ISR components ATF4, GADD34, CHOP, and DR5, suggesting hardwired molecular timers regulate ISR behaviors. Our combined experimental and computational analyses reveal limiting ATF4 levels, which can be suppressed when TC levels drop below a threshold that would allow its translation. While our model accurately predicts this initial saturation limit, its divergence from the data at high stress levels, correlated with minimal TC levels, identified a "translational cliff" that defines a finite ATF4-dependent ISR operational range. This work establishes a quantitative platform to probe ISR dynamics and generate novel, testable hypotheses.

systems biology↗

bioRxiv2025

Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics

Persistent activation of the integrated stress response (ISR) is a major driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. Using a new mouse model (Ppp1r15bR658C mice) that mimics the persistent ISR activation and cognitive decline observed in humans, we generated the first single-cell ISR atlas of the brain. By integrating single-cell RNA-seq and single-cell ATAC-seq with proteomics, we discovered that distinct brain cell types respond differently to persistent ISR activation and elicit cell-type-specific ISR programs. Interestingly, chromatin accessibility analyses revealed that the ISR downstream factor ATF4 is a key ISR effector in GABAergic neurons, while AP-1 (JUNB) is implicated in glutamatergic neurons. More importantly, selective deletion of ATF4 in GABAergic neurons--but not in glutamatergic neurons--impacts ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on unique ISR downstream effectors to regulate mnemonic processes. Furthermore, we defined a comprehensive molecular signature of persistent ISR activation, which we showed could serve as a biomarker for cognitive dysfunction across neurodevelopmental, neurodegenerative disorders and normal aging. This multi-omic framework provides a key platform for exploring and validating new scientific hypotheses, significantly advancing our understanding of ISR-related brain disorders.

neuroscience↗

bioRxiv2024

Fate mapping of peripherally derived macrophages reveals a long-lasting engrafted population that maintains a distinct transcriptomic profile for up to 8 months after Traumatic Brain Injury

Traumatic Brain Injury (TBI) is one of the most established environmental risk factors for the development of dementia and long term neurological deficits representing a critical health problem for our society. It is well-established that TBI-induced neuroinflammation contributes to the long-lasting cognitive deficits and engages brain-resident macrophages (microglia) as well as monocytes-derived macrophages (MDMs) recruited from the periphery. While numerous studies have characterized microglia response to TBI, and the critical role of early infiltrated MDMs in the development of cognitive dysfunctions, the fate of MDMs in TBI remains unknown. Microglia and MDMs have distinct embryological origins and it is unclear if MDMs can fully transition to microglia after infiltrating the brain. This gap in knowledge is due to the fact that after brain engraftment, MDMs stop expressing their signature markers, thus making discrimination from resident microglia cells elusive. Here, for the first time, we longitudinally trace the fate of MDMs by taking advantage of two complementary yet distinct fate mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, where inflammatory monocytes are permanently labeled even after in situ reprogramming. We demonstrated that early infiltrated MDMs persist in the brain for up to 8 months after TBI in adult female and male mice. Notably, MDMs retain their phagocytic activity while remaining transcriptomically distinct from microglia, and show a signature associated with aging and disease. Our data significantly advance the understanding of long-lasting MDMs and provide critical knowledge for developing more targeted therapeutic interventions for myeloid cells.

immunology↗