Ubiquitin-dependent sorting of integral membrane proteins for degradation in lysosomes

Abstract

The pathways that deliver newly synthesized proteins that reside in lysosomes are well understood on comparison with our knowledge of how integral membrane proteins are sorted and delivered to the lysosome for degradation. Many membrane proteins are sorted to lysosomes following ubiquitination, which provides a sorting signal that can operate for sorting at the TGN (trans-Golgi network), at the plasma membrane or at the endosome for delivery into lumenal vesicles. Candidate multicomponent machines that can potentially move ubiquitinated integral membrane cargo proteins have been identified, but much work is still required to ascertain which of these candidates directly recognize ubiquitinated cargo and what they do with cargo after recognition. In the case of the machinery required for sorting into the lumenal vesicles of endosomes, other functions have also been determined including a link between sorting and movement of endosomes along microtubules.

Figure 1

Ub is used as a sorting signal in post-Golgi membrane traffic pathways. The diagram shows three sites at which Ub is known to act as a sorting signal for membrane proteins: TGN, plasma membrane and endosome. Some known components of Ub interacting sorting machinery are indicated.

Figure 2

The ESCRT pathway for sorting ubiquitinated proteins at the endosome. In yeast genetic screens have identified 18 genes encoding Vps proteins required to sort ubiquitinated membrane proteins into the lumenal vesicles of MVBs. Thirteen of these form 3 ESCRT complexes, including an extended ESCRT-III complex of 6 similar alpha-helical proteins. Also shown is the Na+/H+ exchanger, which contributes in an unkown way to a pH-dependent process involved in MVB formation. The diagram shows a model in which the Hrs-STAM complex binds to ubiquitinated cargo within clathrin enriched endosomal subdomains. Ub-cargo is then recognized by Ub-binding domains of ESCRT-I and/or ESCRT-II prior to delivery into forming intralumenal vesicles. Following recruitment of ESCRT-III and ESCRT-III associated proteins, ATP hydrolysis by Vps4p results in depolymerisation. Dub indicates a de-ubiquitinating enzyme.