Introduction to our Research
1. Endosomal sorting
The
endosomal system comprises a series of functionally and morphologically heterogenous
membrane compartments that are dynamically interconnected and function in
the sorting and dispatching of cargo to specific cellular destinations. Following
internalisation, receptors like those for the cation-independent mannose 6-phosphate
(CI-MPR), transferrin (TfnR) and epidermal growth factor (EGFR) enter the
early endosome from where a series of sorting events segregate them into separate
trafficking iteniaries. The TfnR is recycled back to the plasma membrane either
through a fast recycling route or, more slowly, via the juxtanuclear endocytic
recycling compartment (ERC). In contrast, the EGFR is retained within the
limiting membrane of the early endosome through recognition of a ubiquitin
tag. This results in the ESCRT-mediated sorting of the receptor into intraluminal
vesicles of the early endosome. These mature into late endosomes/multivesicular
bodies (MVBs) that become competent to fuse with lysosomes, leading to EGFR
degradation. Finally, the CI-MPR is sorted for retrieval back to the trans-Golgi
network (TGN) through both early and late endosomal pathways (image taken
from Cullen: Nat. Rev. Mol. Cell Biol. 9, 574-582 (2008)).
2. Tubular and vesicular complexities of the endosomal network
A
more complexed model of cargo sorting within the early endocytic network is
emerging. Associated with the vacuolar region of the early endosome is a network
of tubular profiles that have been variously refered to as the tubular sorting
endosome (TSE)’ or ‘tubular endosomal network (TEN)’. These,
and related tubular profiles like the “endosome-to-TGN transport carrier”
(ETC), function as endosomal subdomains into which proteins are sorted for
transport to specific cellular destinations. Carriers subsequently leave these
subdomains transporting their cargo to specific cellular destinations. We
know very little about how such tubular subdomains are formed or the functional
components that define their architecture. Moreover, we do not understand
how sorting is coupled with the formation and dynamics of these tubular ultra-structures.
That said, one family of proteins increasingly being linked with these fundamental
events are the sorting nexins (image taken from Cullen: Nat. Rev. Mol. Cell
Biol. 9, 574-582 (2008)).
3. Mammalian sorting nexins
Sorting nexins (SNXs) are a family of proteins classified by the presence of a particular type of phox-homology (PX) domain – the SNX-PX domain. These proteins have been identified across phyla, from yeast through to mammals - currently 10 yeast and 33 mammalian sorting nexins have been annotated. As PX domains function, in the most part, by binding phosphatidylinositol 3-monophosphate (PtdIns(3)P), sorting nexins are associated with PtdIns(3)P-enriched elements of the early endocytic network. From here they play diverse roles in endocytosis, endosomal sorting and endosomal signalling.
For
mammalian sorting nexins, three distinct sub-families have been described:
SNX-BAR proteins (besides the SNX-PX domain these proteins also contain a
C-terminal BAR domain), SNX-PX proteins (these appear to solely contain the
SNX-PX domain) and the SNX-other proteins (in addition to the SNX-PX domain
these proteins containing other motifs many of which appear to play a role
in signalling). It should be stressed that because sorting nexin proteins
are group through the presence of a SNX-PX domain it does not necessarily
follow that all proteins will be involved in sorting events. Indeed, some
sorting nexins appear to be involved in endosomal signalling (image taken
from Cullen: Nat. Rev. Mol. Cell Biol. 9, 574-582 (2008)).