TY  - BOOK
AU  - Ahn,G.
AU  - Riley,N.M.
AU  - Kamber,R.A.
AU  - Wisnovsky,S.
AU  - Moncayo Von Hase,S.
AU  - Bassik,M.C.
AU  - Bertozzi,C.R.
TI  - Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras
N2  - Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs)harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells. We found that disrupting retromer genes improved target degradation by reducing LYTAC recycling to the plasma membrane. Neddylated cullin-3 facilitated LYTAC-complex lysosomal maturation and was a predictive marker for LYTAC efficacy. A substantial fraction of cell surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Thus, inhibition of M6P biosynthesis increased the internalization of LYTAC-target complexes. Our findings inform design strategies for next-generation LYTACs and elucidate aspects of cell surface receptor occupancy and trafficking
UR  - https://drive.google.com/file/d/1KlBnW2344dudiFqiedK60ARHK4ei1AiW/view?usp=drivesdk
ER  -