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9.A.48 The Unconventional Protein Secretion (UPS) System Family

Mammalian cells export most proteins by the endoplasmic reticulum/Golgi-dependent pathway. However, some proteins are secreted via unconventional mechanisms. The latter include the proinflammatory cytokines interleukin(IL)-1β, IL-18, and IL-33, which require activation by caspase-1 for biological activity. Caspase-1 itself is activated by innate immune complexes, the inflammasomes. Secretion of the leaderless proteins proIL-1α, caspase-1, and fibroblast growth factor (FGF)-2 (see TC# 1.A.108) depends on caspase-1 activity (Keller et al., 2008). Although proIL-1alpha and FGF-2 are not substrates of the protease, they interact physically. Secretome analysis using iTRAQ proteomics revealed caspase-1-mediated secretion of other leaderless proteins with known or unknown extracellular functions. Many of these proteins are involved in inflammation, cytoprotection, or tissue repair. Thus, caspase-1 plays a role in unconventional protein secretion. By this mechanism, stress-induced activation of caspase-1 directly links inflammation to cytoprotection, cell survival, and regenerative processes (Keller et al., 2008). Non-conventional export of cytoplasmic proteins has been reviewed (Ebner and Götz 2018).

A growing number of proteins devoid of signal peptides have been shown to be released through non-classical pathways independent of the endoplasmic reticulum and Golgi. Among them are two potent proangiogenic cytokines, FGF1 (TC# 1.A.108) and IL1α (TC# 1.A.109). Stress-induced transmembrane translocation of these proteins requires the assembly of copper-dependent multiprotein release complexes. It involves the interaction of exported proteins with the acidic phospholipids of the inner leaflet of the cell membrane and membrane destabilization. Not only stress, but also thrombin treatment and inhibition of Notch signaling stimulate the export of FGF1 (Prudovsky et al., 2008).

Stress enhances the expression of S100A13 and induces the actin cytoskeleton-dependent translocation of FGF1, S100A13, and p40 Syt1 to the inner leaflet of the cell membrane where they bind to acidic phospholipids. SK1, located on the inner leaflet of the cell membrane, serves as a source of copper ions (which are provided to SK1 by the transmembrane copper transporters). Copper delivered by SK1 is required for the formation of the release complex. This complex includes the covalent FGF1 dimer, non-covalent S100A13 dimer, p40 Syt1 and SK1. The release complex binds to Anx II, which is also located on the inner leaflet of the cell membrane (Pompa et al. 2017). Transmembrane flipping of acidic phospholipids results in the export of the FGFI release complex and Anx II (Prudovsky et al., 2008) (Giuliani et al., 2011). Galectin-3 may form pores in the plasma membrane that facilitate it's secretion to the outside (Pompa et al. 2017).

There are two non-conventional routes: One sustains the extracellular delivery of cytoplasmic proteins that lack a signal peptide, the other supports the transport of transmembrane proteins to the plasma membrane in a manner that bypasses the Golgi. Some unconventional secretion events are triggered by cellular stress as noted above (Rabouille 2016). A Golgi protein, Golgi Re-Assembly and Stacking Protein (GRASP; Q99JX3), has been shown to be essential to both types of unconventional secretion.

References associated with 9.A.48 family:

Ahat, E., S. Bui, J. Zhang, F. da Veiga Leprevost, L. Sharkey, W. Reid, A.I. Nesvizhskii, H.L. Paulson, and Y. Wang. (2022). GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin. J. Biol. Chem. 298: 102219. [Epub: Ahead of Print] 35780830
Ebner, P. and F. Götz. (2018). Bacterial Excretion of Cytoplasmic Proteins (ECP): Occurrence, Mechanism, and Function. Trends Microbiol. [Epub: Ahead of Print] 30442534
Giuliani, F., A. Grieve, and C. Rabouille. (2011). Unconventional secretion: a stress on GRASP. Curr. Opin. Cell Biol. 23: 498-504. 21571519
Hirai, Y., C.M. Nelson, K. Yamazaki, K. Takebe, J. Przybylo, B. Madden, and D.C. Radisky. (2007). Non-classical export of epimorphin and its adhesion to alphav-integrin in regulation of epithelial morphogenesis. J Cell Sci 120: 2032-2043. 17535848
Keller, M., A. Rüegg, S. Werner, and H.D. Beer. (2008). Active caspase-1 is a regulator of unconventional protein secretion. Cell 132: 818-831. 18329368
Lai, Y., X. Lou, Y. Jho, T.Y. Yoon, and Y.K. Shin. (2013). The synaptotagmin 1 linker may function as an electrostatic zipper that opens for docking but closes for fusion pore opening. Biochem. J. 456: 25-33. 24001110
Pompa, A., F. De Marchis, M.T. Pallotta, Y. Benitez-Alfonso, A. Jones, K. Schipper, K. Moreau, V. Žárský, G.P. Di Sansebastiano, and M. Bellucci. (2017). Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology. Int J Mol Sci 18:. 28346345
Prudovsky, I., F. Tarantini, M. Landriscina, D. Neivandt, R. Soldi, A. Kirov, D. Small, K.M. Kathir, D. Rajalingam, and T.K. Kumar. (2008). Secretion without Golgi. J. Cell. Biochem. 103: 1327-1343. 17786931
Rabouille, C. (2016). Pathways of Unconventional Protein Secretion. Trends Cell Biol. [Epub: Ahead of Print] 27989656