Unconventional protein secretion – new insights into the pathogenesis and therapeutic targets of human diseases

Abstract

Most secretory proteins travel through a well-documented conventional secretion pathway involving the endoplasmic reticulum (ER) and the Golgi complex. However, recently, it has been shown that a significant number of proteins reach the plasma membrane or extracellular space via unconventional routes. Unconventional protein secretion (UPS) can be divided into two types: (i) the extracellular secretion of cytosolic proteins that do not bear a signal peptide (i.e. leaderless proteins) and (ii) the cell-surface trafficking of signal-peptide-containing transmembrane proteins via a route that bypasses the Golgi. Understanding the UPS pathways is not only important for elucidating the mechanisms of intracellular trafficking pathways but also has important ramifications for human health, because many of the proteins that are unconventionally secreted by mammalian cells and microorganisms are associated with human diseases, ranging from common inflammatory diseases to the lethal genetic disease of cystic fibrosis. Therefore, it is timely and appropriate to summarize and analyze the mechanisms of UPS involvement in disease pathogenesis, as they may be of use for the development of new therapeutic approaches. In this Review, we discuss the intracellular trafficking pathways of UPS cargos, particularly those related to human diseases. We also outline the disease mechanisms and the therapeutic potentials of new strategies for treating UPS-associated diseases.

Iron Limitation in Klebsiella pneumoniae Defines New Roles for Lon Protease in Homeostasis and Degradation by Quantitative Proteomics

“…These potential roles for Lon protease in the extracellular environment are very intriguing and warrant further study. Moreover, our detection of proteins undergoing both conventional (e.g., signal peptide, transmembrane domain) and non-conventional (e.g., membrane-associated, guilt-by-association) modes of secretion, along with overlap between the secretome and OMV profiles, and the presence of proteases in extracellular bacterial vesicles further supports the presence of Lon protease in the extracellular environment (Dalbey et al, 2012;Lee et al, 2012;Cezairliyan and Ausubel, 2017;Kim et al, 2018). We also compare the abundance profiles of vesicle-associated K. pneumoniae proteins and observe an overall increase in vesicle-associated proteins under limited vs. replete iron conditions.…”

The ArathEULS3 Lectin Ends up in Stress Granules and Can Follow an Unconventional Route for Secretion

“…In our research, no additional vesicular structures were observed during microscopy. In mammalian cells and yeast, several examples of LPs were described to be secreted through plasma membrane pore formation or by ABC transporters anchored in the plasma membrane, such as, e.g., described for interleukin (IL)-1β, fibroblast growth factors, and the HIV transactivator of transcription [44]. In plants, direct translocation across the plasma membrane was not discovered yet.…”

Identification of Rabbit Oviductal Fluid Proteins Involved in Pre‐Fertilization Processes by Quantitative Proteomics

“…Cells can utilize various unconventional secretory mechanisms to release proteins . There is now growing evidence that unconventional secretory routes can markedly contribute to the presence of intracellular proteins in the extracellular space (e.g., annexins, ANXAs; heat shock protein 70, HSP70; interleukin 1‐beta, IL‐1ß) . Thus, it seems reasonable that Oecs release specific proteins like HSPs via unconventional mechanisms.…”