Publication: The interactomics of sortilin: an ancient lysosomal receptor evolving new functions
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Date
2009
Authors
Canuel, Maryssa ; Libin, Yuan ; Morales, Carlos R.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
The delivery of soluble lysosomal proteins to
the lysosomes is dependent primarily on the mannose 6-
phosphate receptor (MPR). The MPR has been
demonstrated to attain the early endosomes via a process
that requires the interaction of its cytosolic domain with
the GGA and AP-1 adaptor proteins. Additionally, the
MPR can be recycled back to the trans-Golgi network
(TGN) through its interaction with the retromer
complex. Interestingly, in I-cell disease (ICD), in which
the MPR pathway is non-functional, many soluble
lysosomal proteins continue to traffic to the lysosomes.
This observation led to the discovery that sortilin is
responsible for the MPR-independent targeting of the
sphingolipid activator proteins (SAPs) and acid
sphingomyelinase (ASM). More recently, our laboratory
has tested the hypothesis that sortilin is also capable of
sorting a variety of cathepsins that exhibit varying
degrees of MPR-independent transport. We have
demonstrated that the transport of cathepsin D is
partially dependent upon sortilin, that cathepsin H
requires sortilin, and that cathepsins K and L attain the
lysosomes in a sortilin-independent fashion. As a type-1
receptor, sortilin also has numerous cytosolic binding
partners. It has been observed that like the MPR, the anterograde trafficking of sortilin and its cargo require
both GGAs and AP-1. Similarly, the retrograde recycling
pathway of sortilin also involves an interaction with
retromer through a YXXf site in the cytosolic tail of
sortilin. In conclusion, the cytosolic domains of sortilin
and MPR possess a high degree of functional homology
and both receptors share a conserved trafficking
mechanism.
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