Most eukaryotic proteins are secreted through the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. However, cytoplasmic, nuclear and signal-peptide-containing proteins have been shown to reach the cell surface by non-conventional transport pathways. The mechanisms and molecular components of unconventional protein secretion are beginning to emerge, including a role for caspase 1 and for the peripheral Golgi protein GRASP, which could function as a plasma membrane tether for membrane compartments during specific stages of development.

The vast majority of extracellular proteins are exported from mammalian cells by the endoplasmic reticulum/ Golgi-dependent secretory pathway. For poorly understood reasons, however, a heterogenous group of extracellular proteins has been discovered that does not make use of signal peptide-dependent secretory transport. Both the release mechanisms and the molecular identity of the secretory machines involved have remained elusive. Recent studies now have established a subgroup of unconventional secretory proteins capable of translocating from the cytoplasm directly across the plasma membrane to get access to the exterior of eukaryotic cells. This review aims to focus on a detailed comparison of the subcellular site of membrane translocation of various unconventional secretory proteins such as the proangiogenic molecule fibroblast growth factor-2 (FGF-2) and Leishmania hydrophilic acylated surface protein B (HASP B). A potential link between membrane translocation and quality control as an integral part of unconventional secretory processes is discussed.

The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells. Using a series of binding assays, we show that free tau interacts with components enriched at the inner leaflet of the plasma membrane, finally leading to its translocation across the plasma membrane mediated by sulfated proteoglycans. We provide further evidence that secreted soluble tau species spread trans-cellularly and are sufficient for the induction of intracellular tau aggregation in adjacent cells. Our study demonstrates the mechanistic details of tau secretion and provides insights into the initiation and progression of tau pathology.

COPI-coated vesicle budding from lipid bilayers whose composition resembles mammalian Golgi membranes requires coatomer, ARF, GTP, and cytoplasmic tails of putative cargo receptors (p24 family proteins) or membrane cargo proteins (containing the KKXX retrieval signal) emanating from the bilayer surface. Liposome-derived COPI-coated vesicles are similar to their native counterparts with respect to diameter, buoyant density, morphology, and the requirement for an elevated temperature for budding. These results suggest that a bivalent interaction of coatomer with membrane-bound ARF[GTP] and with the cytoplasmic tails of cargo or putative cargo receptors is the molecular basis of COPI coat assembly and provide a simple mechanism to couple uptake of cargo to transport vesicle formation.

The classical secretion of soluble proteins and transport of integral membrane proteins to the cell surface require transit into and through the endoplasmic reticulum and the Golgi apparatus. Signal peptides or transmembrane domains target proteins for translocation into the lumen or insertion into the membrane of the endoplasmic reticulum, respectively. Here we discuss two mechanisms of unconventional protein targeting to plasma membranes, i.e., transport processes that are active in the absence of a functional Golgi system. We first focus on integral membrane proteins that are inserted into the endoplasmic reticulum but that, however, are transported to plasma membranes in a Golgi-independent manner. We then discuss soluble secretory proteins that are secreted from cells without any involvement of the endoplasmic reticulum and the Golgi apparatus.