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Unconventional Protein Secretion – New Insights Into the Pathogenesis and Therapeutic Targets of Human Diseases Jiyoon Kim, Heon Yung Gee and Min Goo Lee*

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Unconventional Protein Secretion – New Insights Into the Pathogenesis and Therapeutic Targets of Human Diseases Jiyoon Kim, Heon Yung Gee and Min Goo Lee* © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs213686. doi:10.1242/jcs.213686 REVIEW ARTICLE SERIES: CELL BIOLOGY AND DISEASE Unconventional protein secretion – new insights into the pathogenesis and therapeutic targets of human diseases Jiyoon Kim, Heon Yung Gee and Min Goo Lee* ABSTRACT the cell. However, discoveries over the last two decades have shown Most secretory proteins travel through a well-documented that an increasing number of proteins use alternative secretory conventional secretion pathway involving the endoplasmic reticulum pathways that do not involve the ER-to-Golgi transport (Malhotra, (ER) and the Golgi complex. However, recently, it has been shown 2013; Ponpuak et al., 2015; Rabouille, 2017). These alternative that a significant number of proteins reach the plasma membrane or pathways include the extracellular secretion of cytosolic proteins extracellular space via unconventional routes. Unconventional that do not bear a signal peptide (i.e. leaderless proteins) (Rubartelli, protein secretion (UPS) can be divided into two types: (i) the 1997), and cell-surface trafficking of transmembrane proteins via a extracellular secretion of cytosolic proteins that do not bear a signal Golgi-bypassing route. These pathways are collectively referred to peptide (i.e. leaderless proteins) and (ii) the cell-surface trafficking of as unconventional protein secretion (UPS) (see Box 1). signal-peptide-containing transmembrane proteins via a route that With a few exceptions, most UPS pathways are induced by bypasses the Golgi. Understanding the UPS pathways is not only various cellular stresses, such as nutrient starvation (Cruz-Garcia important for elucidating the mechanisms of intracellular trafficking et al., 2014), mechanical stress (Schotman et al., 2008), pathways but also has important ramifications for human health, inflammation (Schroder and Tschopp, 2010) and ER stress (Gee because many of the proteins that are unconventionally secreted by et al., 2011; Jung et al., 2016). Notably, many disease conditions are mammalian cells and microorganisms are associated with human associated with various stresses at the cellular or organismal level diseases, ranging from common inflammatory diseases to the lethal (Fulda et al., 2010), indicating the potential of UPS as a promising genetic disease of cystic fibrosis. Therefore, it is timely and emerging target for the development of novel therapeutics to treat appropriate to summarize and analyze the mechanisms of UPS associated human disease. involvement in disease pathogenesis, as they may be of use for the The number of defined UPS-related diseases continues to expand. ’ development of new therapeutic approaches. In this Review, we For example, sterile inflammation related to Alzheimer s disease, discuss the intracellular trafficking pathways of UPS cargos, allergic and autoimmune diseases, and diabetes can be a trigger to particularly those related to human diseases. We also outline the induce unconventional protein secretion (Agosta et al., 2014; Chen disease mechanisms and the therapeutic potentials of new strategies et al., 2015; Freigang et al., 2013; Gardella et al., 2002; Schroder for treating UPS-associated diseases. and Tschopp, 2010). Heat shock proteins (HSPs) that are secreted unconventionally play a pivotal role in the immunomodulation, KEY WORDS: Unconventional secretion, Human disease, proliferation, angiogenesis and invasiveness of cancer (Rodriguez Pathogenesis, Therapeutic target, Leaderless protein et al., 2009; Sarikonda et al., 2015; Zhang et al., 2012). A number of autophagy components, the mutations of which are involved in Introduction various diseases (Jiang and Mizushima, 2014), participate in UPS of According to the classic principle of protein secretion, cargo numerous cargo proteins (Duran et al., 2010; Kinseth et al., 2007; proteins travel by using the conventional pathway from the Manjithaya et al., 2010). Several mutant transmembrane proteins, endoplasmic reticulum (ER) to the Golgi complex, from which whose associated trafficking defects to the cell surface cause they subsequently move to the trans-Golgi network (TGN) and inherited genetic disorders, such as cystic fibrosis and congenital finally to the plasma membrane (Lee et al., 2004). This process is hearing loss can, alternatively, reach the plasma membrane by initiated by recognition of a signal peptide (also known as ‘leader Golgi-bypassing UPS (Gee et al., 2011; Jung et al., 2016). In sequence’) at the N-terminus or transmembrane domain of cargo addition, UPS has even been shown to be essential for proteins, followed by sequential budding and fusion of vesicular microorganisms to mediate their extracellular release and exert carriers (Bonifacino and Glick, 2004). Each step of the secretion biotrophic pathogenicity (Shoji et al., 2014). pathway is under the control of a number of regulatory proteins. Recent developments in the field have contributed to significant Correct regulation of the classic secretory pathway is imperative for advances in the understanding of the molecular processes involved the life and health of the organism (Viotti, 2016). Since the in UPS (Daniels and Brough, 2017; Pompa et al., 2017; Ponpuak discovery of vesicular exocytic mechanisms, this classic protein et al., 2015; Rabouille, 2017; Santos et al., 2017). Nevertheless, a secretion pathway involving ER-to-Golgi transport has been comprehensive description that adequately explains the role in UPS considered the only standard mechanism to move proteins out of in disease pathogenesis is currently lacking. In this Review, we will define emerging roles for UPS in disease pathogenesis and highlight the possibility of novel therapeutics that target UPS. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea. Disease-associated unconventional secretion pathways Overview and classification *Author for correspondence ([email protected]) With the increased scientific understanding of the alternative M.G.L., 0000-0001-7436-012X secretion pathways, several researchers have attempted to Journal of Cell Science 1 REVIEW Journal of Cell Science (2018) 131, jcs213686. doi:10.1242/jcs.213686 Leaderless non-vesicular UPS – Types I and II Box 1. Conventional and unconventional protein The leaderless non-vesicular class of UPS includes cytoplasmic secretion pathways leaderless proteins that are secreted directly out of the cell either Most secretory proteins reach their destination via the ER–Golgi-target through plasma membrane pores (Type I) (Steringer et al., 2012) or organelle route, which is referred to as the ‘classic’ or ‘conventional’ protein through ABC transporters (Type II) (McGrath and Varshavsky, secretion pathway. These secretory proteins contain a signal peptide 1989). One of several typical triggers for this type of UPS is ‘ ’ (the leader sequence ) that directs their translocation into the lumen or to inflammation, which leads to the extracellular release of diverse the ER membrane. The newly synthesized proteins then exit the ER at an ER-exit site (ERES) through coat protein complex II (COPII)-coated cytokines that do not possess a signal peptide (Schroder and vesicles and, so, reach the Golgi network before being dispatched to the Tschopp, 2010). A well-known example of a protein that utilizes plasma membrane, lysosomes, endosomes or peroxisomes (Gee et al., this UPS is interleukin (IL)-1β, which is mainly expressed in 2018; Viotti, 2016). Fusion of vesicular intermediates and organelles is myeloid cells, such as macrophages and monocytes. Initially, IL-1β mediated by soluble N-ethylmaleimide-sensitive factor (NSF) attachment is produced as a 31-kDa inactive form that is cleaved by caspase-1 protein (SNAP) receptor proteins (SNAREs), Rab proteins and their into the 17-kDa mature form. The latter is then recruited by the regulators (Mellman and Warren, 2000). In addition to the above-mentioned conventional pathway, eukaryotic intracellular NACHT-domain-, LRR-motif- and PYD-containing cells also utilize unconventional protein secretion (UPS) for protein sorting protein3 (NLRP3) component of the inflammasome, thus engaging and delivery. Initially, the term ‘unconventional secretion’ was used for the the immune response (Schroder and Tschopp, 2010). It appears that release of cytoplasmic proteins that lack a signal peptide, i.e. leaderless multiple UPS pathways can mediate IL-1β secretion (see below, proteins, into the extracellular medium. Later, it was found that some ‘Leaderless vesicular UPS - Type III’), depending on inflammatory transmembrane proteins that are synthesized in the ER, reach the plasma conditions and cell type. Secretion of IL-1β from macrophages membrane via a route that bypasses the Golgi complex (Nickel and Rabouille, 2009). As described in the text, Rabouille colleagues divided following inflammation is mediated by a type of UPS that requires UPS into four types, i.e. Type I, II and III UPS of leaderless proteins, and hyper-permeabilization of the plasma membrane (Bergsbaken et al., Type IV UPS of Golgi-bypassing transmembrane proteins (Rabouille et al., 2009; Martín-Sánchez et al., 2016). The precise mechanism of this 2012). However, the ABC transporter-mediated Type II pathway is not well membrane hyper-permeabilization is not yet fully understood studied and needs additional validation (Rabouille, 2017). (Rabouille, 2017),
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