Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation.

Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease.

The Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells.

PIX proteins are guanine nucleotide exchange factors (GEFs) that activate Rac and Cdc42, and are known to have numerous functions in various cell types. Here, we show that a PIX protein has an important function in muscle. From a genetic screen in C.

Animal models of sarcopenia.

Sarcopenia is the age-related decline in muscle mass and function without any underlying disease. The exact molecular mechanisms responsible for this pathology remain unknown. The use of model organisms, such as mice, rats, flies, and worms, has advanced the field of sarcopenia research by identifying therapeutic strategies and genetic mutations that result in improved muscle mass and function of elderly animals.

Mutational Analysis of the Structure and Function of the Chaperoning Domain of UNC-45B.

UNC-45B is a multidomain molecular chaperone that is essential for the proper folding and assembly of myosin into muscle thick filaments in vivo. It has previously been demonstrated that the UCS domain is responsible for the chaperone-like properties of the UNC-45B. To better understand the chaperoning function of the UCS domain of the UNC-45B chaperone, we engineered mutations designed to 1) disrupt chaperone-client interactions by removing and altering the structure of a putative client-interacting loop and 2) disrupt chaperone-client interactions by changing highly conserved residues in a putative client-binding groove.

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development.

Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases.

Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.

Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage.