Trafficking and proteolytic processing of RNF13, a model PA-TM-RING family endosomal membrane ubiquitin ligase

RING finger protein 13 (RNF13) is a ubiquitously expressed, highly regulated ubiquitin ligase anchored in endosome membranes. A RING domain located in the cytoplasmic half of this type 1 membrane protein mediates ubiquitination in vitro but physiological substrates have not yet been identified. The protein localized in endosomal membranes undergoes extensive proteolysis in a proteasome-dependent manner, but the mRNA level can be increased and the encoded protein stabilized under specific physiological conditions. The cytoplasmic half of RNF13 is released from the membrane by regulatory proteases and therefore has the potential to mediate ubiquitination at distant sites independent of the full-length protein. In response to protein kinase C activation, the full-length protein is stabilized and moves to recycling endosomes and to the inner nuclear membrane, which exposes the RING domain to the nucleoplasm. Thus RNF13 is a ubiquitin ligase that can potentially mediate ubiquitination in endosomes, on the plasma membrane, in the cytoplasm, in the nucleoplasm or on the inner nuclear membrane, with the site(s) regulated by signaling events that modulate protein targeting and proteolysis.