TP53INP2 mediates autophagic degradation of ubiquitinated proteins through its ubiquitin-interacting motif.

The tumor protein p53-inducible nuclear protein 2 (TP53INP2) has been reported to participate in autophagy by interacting with autophagosome-localized autophagy-related protein 8 (Atg8) family proteins, including LC3. Here, we uncover a novel function for TP53INP2 in the autophagic degradation of proteins. We identify the ubiquitin-interacting motif (UIM) of TP53INP2 that mediates its binding to ubiquitin and ubiquitinated proteins. TP53INP2 lacking the UIM is able to displace autophagic adaptor p62 from LC3, which leads to accumulation of ubiquitinated proteins in cells. Furthermore, overexpression of TP53INP2 lacking the UIM sensitizes cells to chloroquine treatment. Our findings indicate that TP53INP2 may act as a novel autophagic adaptor through recruiting ubquitinated substrates to autophagosomes for degradation.