Cell biology of membrane trafficking in human disease

Abstract

Understanding the molecular and cellular mechanisms underlying membrane traffic pathways is crucial to the treatment and cure of human disease. Various human diseases caused by changes in cellular homeostasis arise through a single gene mutation(s) resulting in compromised membrane trafficking. Many pathogenic agents such as viruses, bacteria, or parasites have evolved mechanisms to subvert the host cell response to infection, or have hijacked cellular mechanisms to proliferate and ensure pathogen survival. Understanding the consequence of genetic mutations or pathogenic infection on membrane traffic has also enabled greater understanding of the interactions between organisms and the surrounding environment. This review focuses on human genetic defects and molecular mechanisms that underlie eukaryote exocytosis and endocytosis and current and future prospects for alleviation of a variety of human diseases.

Fig. 1

Quality control of protein assembly within the endoplasmic reticulum. Proteins destined for the secretory pathway (this example shows a transmembrane protein) are cotranslationally translocated from the ribosome into the lumen of the endoplasmic reticulum (ER) through a portal referred to as the Sec61 translocon. As the newly synthesized protein enters the ER, quality control mechanisms in the form of protein chaperones bind to it and fold it to its correct conformation. Further processing occurs through interactions with other chaperones before the successfully folded protein is loaded into COPII‐coated vesicles and shuttled from the ER to the Golgi apparatus. However, if the protein carries a mutation that causes it to take on an aberrant conformation the ER chaperones will trigger a misfolded protein response. This has two outcomes: either the chaperones will remain bound to the misfolded protein, preventing its escape from the organelle (ER retention), or the protein will be ubiquitinated and retrotranslocated through the Sec61 complex for proteasomal degradation in the cell cytoplasm. A number of human genetic diseases are a result of key proteins failing to traffic through the secretory pathway and as a consequence are retained or degraded in this manner.

Fig. 2

The secretory pathway and vesicular trafficking. Protein enters the secretory pathway at the endoplasmic reticulum (ER) and is trafficked in COPII‐coated vesicular structures to the intermediate compartment (ERGIC/VTC), from which COPI‐coated vesicles carry it to the cis face of the Golgi. Cargo protein (C) continues along the secretory pathway through the Golgi apparatus to the trans‐Golgi network (TGN). Retention signals in ER resident proteins (R) ensure they undergo retrograde trafficking from the Golgi in COPI vesicles. Retrograde transport of Golgi enzymes that may have escaped their resident cisternae also occurs in COPI‐coated vesicles. At the distal face of the Golgi the TGN ensures the correct targeting of proteins, either constitutively or regulated to the plasma membrane, or to intracellular membrane compartments such as proteolytic or secretory lysosomes.

Fig. 3

Protein trafficking through the endosomal–lysosomal system. Cell surface receptors are internalized through clathrin‐coated vesicles (CCVs) at the plasma membrane. In the cell cytoplasm, CCVs shed their coat components and fuse to produce endosomes. Internalized receptors are either recycled from sorting endosomes (housekeeping receptors, e.g., transferrin receptor) or targeted for degradation within the lysosome (signaling receptors, e.g., growth factor receptors) after movement through the late endosome and multivesicular body (MVB) compartments.