LYTACs: An Emerging Tool for the Degradation of Non‐Cytosolic Proteins

In the last two decades, targeted protein degradation has rapidly gained popularity as a technique to eliminate disease-causing undruggable proteins. Over the years, many tools have been devised to degrade proteins by exploiting natural protein homeostasis machinery available in our body, with LYTACs being the latest to come on board. LYTACs, or lysosome-targeting chimeras, make use of the lysosome degradation pathway by recruiting proteins to lysosome-shuttling receptors located at the cell surface. LYTACs are specifically meant for the degradation of membrane-bound and extracellular proteins, which account for the products of 40 % of all protein-encoding genes. In this highlight, we describe two studies that demonstrate the scope of LYTACs and its advantages over the other protein degradation platforms. In the first study, the LYTAC utilizes the cation-independent mannose-6-phosphate receptor (CI-M6PR), while the second study uses the asialoglycoprotein receptor (ASGPR) which is found only on the surface of liver cells.