Biology subjects

Truttmann, M. C.

Publications and source records attributed to Truttmann, M. C..

7 recordsLinked to original sources

bioRxiv2026

Divergent condensates tune transcriptional responses during stress

Dynamic reorganization of the transcription machinery within nuclear membrane-less compartments is an emergent feature of mammalian stress response, associated with critical cellular decisions. However, mechanisms governing the subcellular formation of these stress-induced condensates and their role in transcription regulation remain poorly understood. Here, we find that heat shock factor 1 (HSF1), transcriptional mediator of protein and cellular homeostasis, forms condensates during various adverse conditions, but these assemblies exhibit context-dependent divergent transcriptional outcomes. During heat shock, HSF1 orchestrates the coordinated assembly of transcription hubs via canonical activation, including post-translational modifications (PTMs), trimerization, and DNA binding. While HSF1s disordered regions restrict condensate formation in unstressed situations, they promote stress-induced condensate maturation to transcriptionally active states. Strikingly, HSF1 condensates that form during other environmental and chemotherapeutic stresses stall at distinct stages of hub formation, assemble independent of PTMs, and exhibit reduced sub-condensate dynamics. These aspects culminate in attenuated genomic occupancy and transcriptional output at HSF1-associated loci, consistent with functional impairment of HSF1 and the transcription machinery via sequestration. Our work suggests that stress-induced transcription factor condensates drive conserved responses during physiological perturbations, but can be inactivated during pathological insults, rationalizing HSF1 and transcriptional dysfunction across degenerative diseases and toxic exposures.

molecular biology↗

bioRxiv2025

HSP-1-Specific Nanobodies Alter Chaperone Function in vitro and in vivo

Targeted regulation of 70 kilodalton Heat Shock Protein (HSP70) chaperones, particularly the essential cognate heat shock protein (HSC70) and its Caenorhabditis elegans ortholog, HSP-1, may hold the key to improving cellular proteostasis and ameliorating aging-associated conditions linked to protein misfolding and aggregation. However, tools to selectively modulate HSP70 chaperone activity remain elusive. In this study, we pioneer the development of two novel nanobodies, B12 and H5, which specifically bind to both recombinant and endogenous HSP-1. We show that these nanobodies, differing by only two amino acids in their complementarity-determining regions, bind specifically to HSP-1 and effectively reduce both HSP-1 ATPase activity and protein folding capacity in a dose-dependent manner in vitro. We further demonstrate in vivo expression of B12, but not H5, in transgenic C. elegans strains reduces heat-stress survival and proteotoxic-stress resistance, mirroring the effects of hsp-1 knockdown via RNA interference. Our findings suggest that these nanobodies can serve as effective and specific tools for modulating HSP-1 chaperone activity in vivo. These discoveries provide a foundation for future research exploring the therapeutic potential of HSP70-targeting nanobodies in aging and protein misfolding diseases.

biochemistry↗

bioRxiv2024

Loss of FIC-1-mediated AMPylation activates the UPRER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity

Targeted regulation of cellular proteostasis machinery represents a promising strategy for the attenuation of pathological protein aggregation. Recent work suggests that the unfolded protein response in the endoplasmic reticulum (UPRER) directly regulates the aggregation and toxicity of expanded polyglutamine (polyQ) proteins. However, the mechanisms underlying this phenomenon remain poorly understood. In this study, we report that perturbing ER homeostasis in Caenorhabditis elegans through the depletion of either BiP ortholog, hsp-3 or hsp-4, causes developmental arrest in worms expressing aggregation-prone polyQ proteins. This phenotype is rescued by the genetic deletion of the conserved UPRER regulator, FIC-1. We demonstrate that the beneficial effects of fic-1 knock-out (KO) extend into adulthood, where the loss of FIC-1-mediated protein AMPylation in polyQ-expressing animals is sufficient to prevent declines in fitness and lifespan. We further show that loss of hsp-3 and hsp-4 leads to distinct, but complementary transcriptomic responses to ER stress involving all three UPRER stress sensors (IRE-1, PEK-1, and ATF-6). We identify the cytosolic HSP70 family chaperone F44E5.4, whose expression is increased in fic-1-deficient animals upon ER dysregulation, as a key effector suppressing polyQ toxicity. Over-expression of F44E5.4, but not other HSP70 family chaperones, is sufficient to rescue developmental arrest in polyQ-expressing embryos upon hsp-3 knock-down. Finally, we show that knock-down of ire-1, pek-1, or atf-6 blocks the upregulation of F44E5.4 in fic-1-deficient worms. Taken together, our findings support a model in which the loss of FIC-1-mediated AMPylation engages UPRER signaling to upregulate cytosolic chaperone activity in response to polyQ toxicity.

cell biology↗

bioRxiv2024

C. elegans behavior, fitness, and lifespan, are modulated by AWB/ASH-dependent death perception.

The ability of the nervous system to initiate intricate goal-directed behaviors in response to environmental stimuli is essential for metazoan survival. In this study, we demonstrate that the nematode Caenorhabditis elegans perceives and reacts to dead conspecifics. The exposure to C. elegans corpses as well as corpse lysates activates sensory neurons AWB and ASH, triggering a glutamate-and acetylcholine-dependent signaling cascade that regulates both immediate (aversion) and long-term (survival) responses to the presence of a death signature. We identify increased adenosine monophosphate (AMP) and cysteine concentrations as chemical fingerprints for the presence of metazoan corpses and show that death cue sensing by AWB and ASH leads to physiological changes which promote reproduction at the expense of lifespan. Our findings illuminate a novel signaling paradigm that allows organisms to detect and interpret the environmental enrichment of intracellular metabolites as a death cue.

animal behavior and cognition↗

bioRxiv2024

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPRER and ER-phagy

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPRER) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPRER induction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

cell biology↗

bioRxiv2021

Deletion of the AMPylase mFICD alters cytokine secretion and affects cognitive plasticity in vivo

Fic domain-containing AMP transferases (fic AMPylases) are conserved enzymes that catalyze the covalent transfer of AMP to proteins. This post-translational modification regulates the function of several proteins, including the ER-resident chaperone Grp78/BiP. Here we introduce a mFICD AMPylase knock-out mouse model to study fic AMPylase function in vertebrates. We find that mFICD deficiency is well-tolerated in unstressed mice. We show that mFICD-deficient mouse embryonic fibroblasts are depleted of AMPylated proteins. mFICD deletion alters protein synthesis and secretion in splenocytes, including that of IgM and IL-1{beta}, without affecting the unfolded protein response. Finally, we demonstrate that older mFICD-/- mice show improved cognitive plasticity. Together, our results suggest a role for mFICD in adaptive immunity and neuronal plasticity in vivo.

molecular biology↗

bioRxiv2017

Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides

Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation - a post-translational protein modification that has emerged as a powerful modulator of HSP70 activity - influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in C.elegans directly affect aggregation properties and associated toxicity of amyloid-{beta} (A{beta}), of a polyglutamine (polyQ)- extended polypeptide and of -synuclein (-syn). Expression of a constitutively active C. elegans AMPylase Fic-1(E274G) under its own promoter expedites aggregation of A{beta} and -syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Over-expression of Fic-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cyto-protective, rather than a cytotoxic role for such protein aggregates.

cell biology↗