Abstract
Lysosomes are sites for the degradation of diverse cellular components. We recently discovered novel lysosomal systems we termed RNautophagy and DNautophagy. In these systems, RNA and DNA, respectively, are directly imported into lysosomes and degraded. A lysosomal membrane protein, LAMP2C was identified as a receptor for these pathways. The short C-terminal cytosolic tail of LAMP2C binds directly to both RNA and DNA. In this study, we examined the mechanisms underlying recognition of nucleic acids by the cytosolic sequence of LAMP2C. We found that the sequence possesses features of the arginine-rich motif, an RNA-recognition motif found in a wide range of RNA-binding proteins. Substitution of arginine residues in the LAMP2C cytosolic sequence completely abolished its binding capacity for nucleic acids. A scrambled form of the sequence showed affinity to RNA and DNA equivalent to that of the wild-type sequence, as is the case for other arginine-rich motifs. We also found that cytosolic sequences of other LAMP family proteins, LAMP1 and CD68/LAMP4, also possess arginine residues, and show affinity for nucleic acids. Our results provide further insight into the mechanisms underlying RNautophagy and DNautophagy, and may contribute to a better understanding of lysosome function.