Timing is everything. That’s especially true when it comes to the activation of enzymes created by the pancreas to break down food. Pancreatic enzymes are packed in secretory granules as precursor molecules called zymogens. In physiological conditions, those zymogens are activated only when they reach the gut, where they get to work releasing and distributing nutrients that we need to survive. If this process fails and the enzymes are prematurely activated within the pancreatic cell, before they are released from the gland, they break down the pancreas itself causing acute pancreatitis. This is a painful disease that ranges from a mild and autolimited process to a severe and lethal condition. Recently, we demonstrated that the pancreatic acinar cell is able to switch on a refined mechanism that could explain the autolimited form of the disease. This is a novel selective form of autophagy named zymophagy, a cellular process to specifically detect and degrade secretory granules containing activated enzymes before they can digest the organ. In this work, we revise the molecules and mechanisms that mediate zymophagy, a selective autophagy of secretory granules. 1. Introduction Autophagy is an evolutionarily preserved cellular process that is responsible for the degradation of long-lived proteins and entire organelles to maintain intracellular homeostasis and to contribute to starvation and stress responses. Macroautophagy involves the formation of double-membrane autophagosomes around cargoes, including larger structures such as organelles and protein aggregates. Autophagosomes then fuse with lysosomes, where the degradation of the cargoes takes place. Both nonselective bulk autophagy and selective autophagy of specific proteins and organelles have been described [1]. Genetic analyses in yeast identified more than 30 conserved components that are required for different steps of autophagy (termed Atg genes) [2]. Recently, several lines of evidence suggest the existence of selective autophagic degradation pathways in physiology and disease, named, selective autophagy [3]. During selective autophagy, single cellular structures, such as protein aggregates and mitochondria are specifically sequestered by autophagosomes. There is emerging evidence suggesting the involvement of ubiquitin in several forms of selective autophagy process. For example, aggregate clearance by autophagy requires ubiquitylation and ubiquitin-binding receptors such as p62 (also known as SQSTM1) [4]. Ubiquitylated artificial substrates are recognized by the autophagy machinery and are
References
[1]
C. Kraft, M. Peter, and K. Hofmann, “Selective autophagy: ubiquitin-mediated recognition and beyond,” Nature Cell Biology, vol. 12, no. 9, pp. 836–841, 2010.
[2]
K. Suzuki and Y. Ohsumi, “Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae,” The FEBS Letters, vol. 581, no. 11, pp. 2156–2161, 2007.
[3]
C. Kraft, F. Reggiori, and M. Peter, “Selective types of autophagy in yeast,” Biochimica et Biophysica Acta, vol. 1793, no. 9, pp. 1404–1412, 2009.
[4]
S. Pankiv, T. H. Clausen, T. Lamark et al., “p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy,” Journal of Biological Chemistry, vol. 282, no. 33, pp. 24131–24145, 2007.
[5]
P. K. Kim, D. W. Hailey, R. T. Mullen, and J. Lippincott-Schwartz, “Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20567–20574, 2008.
[6]
C. Kraft, A. Deplazes, M. Sohrmann, and M. Peter, “Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease,” Nature Cell Biology, vol. 10, no. 5, pp. 602–610, 2008.
[7]
D. Grasso, A. Ropolo, A. Lo Ré et al., “Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death,” Journal of Biological Chemistry, vol. 286, no. 10, pp. 8308–8324, 2011.
[8]
E. C. Thrower, F. S. Gorelick, and S. Z. Husain, “Molecular and cellular mechanisms of pancreatic injury,” Current Opinion in Gastroenterology, vol. 26, no. 5, pp. 484–489, 2010.
[9]
J. L. Frossard, M. L. Steer, and C. M. Pastor, “Acute pancreatitis,” The Lancet, vol. 371, no. 9607, pp. 143–152, 2008.
[10]
H. U Chiari, “BerdieSelbstverdauung des menschlichen Pankreas,” Zeitschrift für Heilkunde, vol. 17, pp. 69–96, 1896.
[11]
R. P. Sah and A. Saluja, “Molecular mechanisms of pancreatic injury,” Current Opinion in Gastroenterology, vol. 27, no. 5, pp. 444–451, 2011.
[12]
H. Helin, M. Mero, H. Markkula, and M. Helin, “Pancreatic acinar ultrastructure in human acute pancreatitis,” Virchows Archiv, vol. 387, no. 3, pp. 259–270, 1980.
[13]
J. A. Williams, “Receptor-mediated signal transduction pathways and the regulation of pancreatic acinar cell function,” Current Opinion in Gastroenterology, vol. 24, no. 5, pp. 573–579, 2008.
[14]
O. Watanabe, F. M. Baccino, M. L. Steer, and J. Meldolesi, “Supramaximal caerulein stimulation and ultrastructure of rat pancreatic acinar cell: early morphological changes during development of experimental pancreatitis,” The American Journal of Physiology, vol. 246, no. 4, pp. G457–G467, 1984.
[15]
G. Adler, C. Hahn, H. F. Kern, and K. N. Rao, “Cerulein-induced pancreatitis in rats: increased lysosomal enzyme activity and autophagocytosis,” Digestion, vol. 32, no. 1, pp. 10–18, 1985.
[16]
F. S. Gorelick, G. Adler, H. F. Kern, et al., “Cerulein-induced pancreatitis,” in The Pancreas: Biology, Pathophysiology and Disease, V. L. W. Go, E. P. DiMagno, J. D. Gardner, et al., Eds., pp. 501–526, Raven Press, New York, NY, USA, 2nd edition, 1993.
[17]
A. Ropolo, D. Grasso, R. Pardo et al., “The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells,” Journal of Biological Chemistry, vol. 282, no. 51, pp. 37124–37133, 2007.
[18]
M. I. Vaccaro, “Autophagy and pancreas disease,” Pancreatology, vol. 8, no. 4-5, pp. 425–429, 2008.
[19]
F. S. Gorelick and E. Thrower, “The acinar cell and early pancreatitis responses,” Clinical Gastroenterology and Hepatology, vol. 7, supplement 11, pp. S10–S14, 2009.
[20]
N. J. Dusetti, Y. Jiang, M. I. Vaccaro et al., “Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation,” Biochemical and Biophysical Research Communications, vol. 290, no. 2, pp. 641–649, 2002.
[21]
M. I. Vaccaro, D. Grasso, A. Ropolo, J. L. Iovanna, and M. C. Cerquetti, “VMP1 expression correlates with acinar cell cytoplasmic vacuolization in arginine-induced acute pancreatitis,” Pancreatology, vol. 3, no. 1, pp. 69–74, 2003.
[22]
M. I. Vaccaro, A. Ropolo, D. Grasso, and J. L. Iovanna, “A novel mammalian trans-membrane protein reveals an alternative initiation pathway for autophagy,” Autophagy, vol. 4, no. 3, pp. 388–390, 2008.
[23]
Y. Tian, Z. Li, W. Hu et al., “C. elegans screen identifies autophagy genes specific to multicellular organisms,” Cell, vol. 141, no. 6, pp. 1042–1055, 2010.
[24]
E. Itakura and N. Mizushima, “Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins,” Autophagy, vol. 6, no. 6, pp. 764–776, 2010.
[25]
D. Grasso, M. L. Sacchetti, L. Bruno et al., “Autophagy and VMP1 expression are early cellular events in experimental diabetes,” Pancreatology, vol. 9, no. 1-2, pp. 81–88, 2009.
[26]
R. Pardo, A. Lo Ré, C. Archange et al., “Gemcitabine induces the VMP1-mediated autophagy pathway to promote apoptotic death in human pancreatic cancer cells,” Pancreatology, vol. 10, no. 1, pp. 19–26, 2010.
[27]
J. Calvo-Garrido and R. Escalante, “Autophagy dysfunction and ubiquitin-positive protein aggregates in Dictyostelium cells lacking Vmp1,” Autophagy, vol. 6, no. 1, pp. 100–109, 2010.
[28]
S. M. B. Nijman, M. P. A. Luna-Vargas, A. Velds et al., “A genomic and functional inventory of deubiquitinating enzymes,” Cell, vol. 123, no. 5, pp. 773–786, 2005.
[29]
V. Kapuria, L. F. Peterson, D. Fang, W. G. Bornmann, M. Talpaz, and N. J. Donato, “Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis,” Cancer Research, vol. 70, no. 22, pp. 9265–9276, 2010.
[30]
K. D. Wilkinson, “Regulation of ubiquitin-dependent processes by deubiquitinating enzymes,” The FASEB Journal, vol. 11, no. 14, pp. 1245–1256, 1997.
[31]
S. M. Millard and S. A. Wood, “Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes,” Journal of Cell Biology, vol. 173, no. 4, pp. 463–468, 2006.
[32]
M. Raraty, J. Ward, G. Erdemli et al., “Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 24, pp. 13126–13131, 2000.
[33]
R. Dawra, R. P. Sah, V. Dudeja et al., “Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis,” Gastroenterology, vol. 141, no. 6, pp. 2210–2217.e2, 2011.
[34]
D. Hashimoto, M. Ohmuraya, M. Hirota et al., “Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells,” Journal of Cell Biology, vol. 181, no. 7, pp. 1065–1072, 2008.
[35]
Y. Nishida, S. Arakawa, K. Fujitani et al., “Discovery of Atg5/Atg7-independent alternative macroautophagy,” Nature, vol. 461, no. 7264, pp. 654–658, 2009.
[36]
N. Mizushima, A. Yamamoto, M. Matsui, T. Yoshimori, and Y. Ohsumi, “In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker,” Molecular Biology of the Cell, vol. 15, no. 3, pp. 1101–1111, 2004.
[37]
O. A. Mareninova, K. Hermann, S. W. French et al., “Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis,” Journal of Clinical Investigation, vol. 119, no. 11, pp. 3340–3355, 2009.
[38]
F. Fortunato and G. Kroemer, “Impaired autophagosome-lysosome fusion in the pathogenesis of pancreatitis,” Autophagy, vol. 5, no. 6, pp. 850–853, 2009.
[39]
A. Kaser and R. S. Blumberg, “Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease,” Gastroenterology, vol. 140, no. 6, pp. 1738–1747, 2011.
