Direct uptake mechanism in lysosome required for neuromuscular homeostasis

Regulated degradation of cellular components plays an essential role in homeostasis. Accumulating evidence indicates the importance of lysosomal degradation of cellular proteins: Dysfunctions in multiple pathways to deliver cytosolic substrates into lysosomes are related to various diseases, including cancers, neurodegenerative diseases, and myopathies. However, much of the effort at understanding such pathways has been devoted to studies on macroautophagy, which entails vast and dynamic rearrangement of membrane structure, and knowledge on other delivery systems and functions of lysosomes per se remains scant. Here, we show that cytosolic proteins are directly imported into lysosomes by a mechanism distinct from any known pathways and degraded. We find that a lysosomal membrane protein, SIDT2, which was previously reported as a putative nucleic acid transporter, is involved in the translocation of substrate proteins in this system. Gain- and loss-of-function analyses reveal that SIDT2 contributes conspicuously to the lysosomal degradation of a wide range of cytosolic proteins in cells at the constitutive level. Furthermore, a dominant-negative type of mutation in SIDT2 causes familial rimmed vacuolar myopathy in humans. Sidt2 knockout mice recapitulated typical features of rimmed vacuolar myopathy, including atrophy and accumulation of cytoplasmic inclusions in skeletal muscles. These results reveal a previously unknown pathway of proteolysis in lysosomes and highlight the importance of noncanonical types of autophagy in human physiology and pathophysiology.