Biology subjects

Brydges, S.

Publications and source records attributed to Brydges, S..

3 recordsLinked to original sources

bioRxiv2024

Lysosomal degradation of ACVR1-Activin complexes negatively regulates signaling of Activins and Bone Morphogenetic Proteins

BMP/TGF{beta} family ligands act mainly as factors that differentially initiate Smad1/5/8 or Smad2/3 signaling via heterotetrameric complexes comprised of two type I and two type II receptors (IIR). ActA (ActA) stands out as it activates Smad2/3 signaling through type I receptor ACVR1B, whereas it generates non-signaling complexes (NSCs) with ACVR1. In fibrodysplasia ossificans progressiva (FOP), a genetic disorder caused by missense mutations in ACVR1 (ACVR1.FOP), ACVR1.FOP*ActA*IIR complexes activate Smad1/5 signaling, mimicking those formed with BMPs. As the NSCs that ActA forms with ACVR1 are stoichiometrically identical with signaling complexes formed with ACVR1.FOP, we explored how NSCs differ from their signaling counterparts. We show that ACVR1*ActA*IIR complexes rapidly traffic to lysosomes, where their constituent components are degraded, reducing the cells responsiveness to BMPs along with ActAs availability. This property is specific to ActA as Activin B, AB, and AC do not form lysosomal trafficking complexes with ACVR1, but rather remain on the surface as NSCs. Lysosomal trafficking and degradation of ACVR1*ActA*IIR complexes is a novel regulatory mechanism of BMP/TGF{beta} signaling whose physiological roles remain largely unexplored.

cell biology↗

bioRxiv2021

ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, Activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by Activin A, an effect countered by inhibition of Activin A via monoclonal antibody treatment. Hence, we surmised that ACVR1 antibodies that block activation of ACVR1 by ligand should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated ACVR1 monoclonal antibodies that block ACVR1s activation by its ligands. Surprisingly, in vivo, these ACVR1 antibodies stimulate HO and activate signaling of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1 and results from ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild type ACVR1 is inhibited by ACVR1 antibodies. These results uncover an additional novel property of FOP-mutant ACVR1 and indicate that ACVR1 antibodies should not be considered as therapeutics for FOP.

biochemistry↗

bioRxiv2020

Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

Lysosomal diseases are a class of genetic disorders predominantly caused by loss of lysosomal hydrolases, leading to lysosomal and cellular dysfunction. Enzyme Replacement Therapy (ERT), where recombinant enzyme is given intravenously, internalized by cells, and trafficked to the lysosome, has been applied to treat several lysosomal diseases. However, current ERT regimens do not correct disease phenotypes in all affected organs because the biodistribution of enzyme uptake does not match that of the affected cells and tissues that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific tissues. The antibody moiety recognizes transmembrane proteins involved in lysosomal trafficking and that are also preferentially expressed in those cells most affected in disease. Using Pompe disease (PD) as an example, we show that targeted ERT is superior to ERT in treating the skeletal muscle phenotypes of PD mice.

bioengineering↗