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Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras

2023; American Association for the Advancement of Science; Volume: 382; Issue: 6668 Linguagem: Inglês

10.1126/science.adf6249

1095-9203

Green Ahn, Nicholas M. Riley, Roarke A. Kamber, Simon Wisnovsky, S. Hase, Michael C. Bassik, Steven M. Banik, Carolyn R. Bertozzi,

Cellular transport and secretion

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.