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090			_aB-20674
245	1	0	_aElucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras
490	0		_vScience, 382(6668), p.eadf6249, 2023
520	3		_aTargeted 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.
700	1	2	_aAhn, G.
700	1	2	_aRiley, N. M.
700	1	2	_aKamber, R. A.
700	1	2	_aWisnovsky, S.
700	1	2	_aMoncayo Von Hase, S.
700	1	2	_aBassik, M. C.
700	1	2	_aBertozzi, C. R.
856	4	0	_uhttps://drive.google.com/file/d/1KlBnW2344dudiFqiedK60ARHK4ei1AiW/view?usp=drivesdk _zPara ver el documento ingresa a Google con tu cuenta: @cicy.edu.mx
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