Our work identifies LYSET as an indispensable component of the biosyn-thetic pathway that directs transport of soluble enzymes to the lysosome. As such, LYSET is essential for entry of diverse, highly pathogenic viruses that rely on endo-lysosomal activation by cathepsins. We uncovered an unexpected molecular mechanism in which LYSET regulates GlcNAc-1-phosphotransferase function by binding to and retaining it in the Golgi apparatus. The key role of LYSET in lysosome biogenesis likely explains MLII-like symptoms observed in patients with LYSET mutations. Altogether, our findings provide insights in fundamental cell physiology with relevance for human inherited disease and viral infection.
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