Figure 1.

Classical trafficking, from the ER to the Golgi to the plasma membrane, is represented by the red arrows. A cargo protein can exit from an ERES in close proximity to the cis-Golgi (route 1a) or a peripheral ERES (route 1b), but irrespective of its ER exit, this protein follows a distinct pathway through the Golgi to the plasma membrane. This pathway is dependent on known SNARE proteins, NSF and SNAPs. As proteins pass from the ER and through the Golgi, their ER-derived high mannose oligosaccharides are modified by addition of complex sugars rendering these proteins EndoH-resistant. BFA treatment or loss of function of intra-Golgi SNAREs would lead to the retention of these proteins in the ER or Golgi and their diminished presence at the plasma membrane.

Potential routes for Golgi bypass are represented by blue arrows. Like classical cargo proteins, Golgi bypass cargoes may exit from an ERES near the cis-Golgi (routes 2a,c) or a peripheral ERES (route 2b). However, the immediate fate of these proteins deviates from the classical pathway. A protein following route 2a (from an ERES near the cis-Golgi) or 2b (from a peripheral ERES) would traffic on ER-derived transport intermediates directly to the plasma membrane, routes perhaps taken by CD45 or αPS1. This route would require a specific set of SNAREs, yet to be identified. As these proteins do not pass through the Golgi stack, their high mannose N-glycans remain sensitive to EndoH. These pathways are also revealed by blocking passage through the Golgi either by the application of BFA, or by the loss of function of intra-Golgi SNAREs, (e.g., Syntaxin 5), and observing their continued transport to the plasma membrane. Proteins that follow route 2c would bypass the Golgi stack via an endosomal intermediate, which would facilitate their delivery to the plasma membrane via conventional endosomal fusion machinery. In the case of CFTR, its exit from the ER may occur from either ERES location to the TGN or endosomes. If it is directly delivered to endosomes, it is likely recycled back to the TGN in which the observed oligosaccharide modifications take place before reaching the plasma membrane.