Mammalian TatD DNase domain containing 1 (TATDN1) is a proteostasis-responsive gene with roles in ventricular structure and neuromuscular function.

The characterization of highly conserved but poorly understood genes often reveals unexpected biological roles, advancing our understanding of disease mechanisms. One such gene is Mammalian TatD DNase domain containing 1 (Tatdn1), the mammalian homolog of bacterial Twin-arginine translocation D (TatD), a protein proposed to have roles either in DNA degradation or protein quality control in unicellular organisms. Despite its association with different pathologies, including several cancer types and cardiovascular diseases, the role of TATDN1 in mammals remains unexplored. Here, we demonstrate that Tatdn1 encodes a cytoplasmic protein that does not participate in DNA degradation but is upregulated in cells under proteostasis stress. Tatdn1-deficient mice exhibit dysregulated expression of genes involved in membrane and extracellular protein biology, along with mild dilated cardiomyopathy and impaired motor coordination. These findings identify TATDN1 as a key player in cytosolic processes linked to protein homeostasis, with significant physiological implications for cardiac and neurological function.