Cargo Capture and Bulk Flow in the Early Secretory Pathway

Abstract

Transport of newly synthesized proteins from the endoplasmic reticulum (ER) to the Golgi complex is highly selective. As a general rule, such transport is limited to soluble and membrane-associated secretory proteins that have reached properly folded and assembled conformations. To secure the efficiency, fidelity, and control of this crucial transport step, cells use a combination of mechanisms. The mechanisms are based on selective retention of proteins in the ER to prevent uptake into transport vesicles, on selective capture of proteins in COPII carrier vesicles, on inclusion of proteins in these vesicles by default as part of fluid and membrane bulk flow, and on selective retrieval of proteins from post-ER compartments by retrograde vesicle transport.

An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling

“…This enrichment of specific cargoes and incorporation of non-retained bystanders into vesicular bulk flow is seen in other examples of vesicle budding (Barlowe and Helenius, 2016) with the notable difference that in intracellular transport, non-specific losses can be recovered by retrieval pathways. Our finding that constitutive ectocytosis removes GPCRs from cilia of Bbs mutants (Fig.…”

ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

“…Our data demonstrate that COPII can in addition exclude resident and misfolded proteins by a factor of 4–9-fold. Comparison with data on BiP suggests that this may be a reasonable measure of the magnitude of the ER retention process: a modified form of BiP lacking the KDEL retrieval signal is secreted from animal cells 5-fold more slowly than a protein tracer of bulk flow (Barlowe and Helenius, 2016; Munro and Pelham, 1987). Thus, by an active sorting mechanism COPII may concentrate cargo and deplete residents, to yield cargo purification of between 25- and 100-fold in a single budding event.…”

“…Resident chaperones and bound folding intermediates make up the majority of ER content and must be retained at that site (Barlowe and Helenius, 2016; Gomez-Navarro and Miller, 2016). A simple model for retention would be for resident proteins to consolidate into immobile networks too large to enter COPII vesicles, but data indicate instead that resident complexes diffuse relatively freely in the ER (Hendershot, 2000; Nehls et al, 2000), leaving the mechanism of ER retention an open problem.…”

“…A simple model for retention would be for resident proteins to consolidate into immobile networks too large to enter COPII vesicles, but data indicate instead that resident complexes diffuse relatively freely in the ER (Hendershot, 2000; Nehls et al, 2000), leaving the mechanism of ER retention an open problem. It is known that residents can escape the ER and are selectively retrieved from post-ER compartments, in particular by the KDEL receptor; however, when the KDEL signal is removed from a resident chaperone, its exit is considerably slower than the bulk flow rate (Barlowe and Helenius, 2016; Munro and Pelham, 1987). We sought to test the hypothesis that COPII-associated machinery restricts the passive uptake into vesicles of mobile resident complexes and associated misfolded proteins.…”

Annexins as Overlooked Regulators of Membrane Trafficking in Plant Cells

“…Two mechanisms of ER-to-Golgi transport of newly synthesized proteins were proposed: non-selective bulk flow and cargo capture [200,201]. In principle, they are not mutually exclusive but rather cooperate to different extents, depending on the type of protein [202]. For bulk-flow the basic protein machinery for ongoing vesicle traffic is sufficient and no additional factors are needed.…”