Autophagy and acute pancreatitis: A novel autophagy theory for trypsinogen activation

Ohmuraya, Masaki; Yamamura, Ken Ichi

doi:10.4161/auto.6825

Cited by 61 publications

(39 citation statements)

References 13 publications

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“…In the cerulein-induced model of experimental pancreatitis, acinar cells develop cytoplasmic vacuoles that are autophagic in origin; these vesicles are involved in the degradation of zymogen granules, leading to the conversion of trypsinogen to trypsin, which accumulates within the acinar cell, triggering cellular self-digestion (23,27,50,58). Autophagy is required for this process, as trypsinogen activation is greatly reduced in mice that lack Atg5 specifically in acinar cells, and cerulein-induced acute pancreatitis does not develop in these mice (27).…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus Infection Induces Autophagy-Like Vesicles and Megaphagosomes in Pancreatic Acinar Cells In Vivo

Kemball¹,

Alirezaei²,

Flynn³

et al. 2010

J Virol

145

182

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Autophagy can play an important part in protecting host cells during virus infection, and several viruses have developed strategies by which to evade or even exploit this homeostatic pathway. Tissue culture studies have shown that poliovirus, an enterovirus, modulates autophagy. Herein, we report on in vivo studies that evaluate the effects on autophagy of coxsackievirus B3 (CVB3). We show that in pancreatic acinar cells, CVB3 induces the formation of abundant small autophagy-like vesicles and permits amphisome formation. However, the virus markedly, albeit incompletely, limits the fusion of autophagosomes (and/or amphisomes) with lysosomes, and, perhaps as a result, very large autophagy-related structures are formed within infected cells; we term these structures megaphagosomes. Ultrastructural analyses confirmed that double-membraned autophagy-like vesicles were present in infected pancreatic tissue and that the megaphagosomes were related to the autophagy pathway; they also revealed a highly organized lattice, the individual components of which are of a size consistent with CVB RNA polymerase; we suggest that this may represent a coxsackievirus replication complex. Thus, these in vivo studies demonstrate that CVB3 infection dramatically modifies autophagy in infected pancreatic acinar cells.Macroautophagy-henceforth referred to as autophagy-is an intracellular process that is important for cellular differentiation, homeostasis, and survival. Through autophagy, longlived cytosolic proteins and organelles become encapsulated within double-membraned vesicles, called autophagosomes, which fuse with lysosomes to facilitate degradation of protein and cellular organelles and to promote nutrient recycling/regeneration. Autophagy plays a key role in the host immune response to infection by viruses, bacteria, fungi, and parasites (reviewed in references 10 and 62). Within virus-infected cells, whole virions and/or viral proteins and nucleic acids are captured inside autophagosomes and degraded (following lysosomal fusion) through the process of xenophagy. Moreover, autophagosome fusion with the endosomal/lysosomal pathway facilitates Toll-like receptor recognition of viral materials and delivers endogenous cytosolic viral proteins to the major histocompatibility complex (MHC) class II antigen presentation pathway, which in turn may help to trigger activation of innate immunity (and type I interferon production) and promote antigen presentation to virus-specific CD4 ϩ T cells (reviewed in references 9, 41, 44, 47, 72, and 90). A recent study has shown that autophagy is also involved in the processing and presentation of MHC class I-restricted viral epitopes (13).Given the importance of autophagy in antiviral immunity, it is perhaps not surprising that viruses have evolved mechanisms to evade and/or subvert this pathway (reviewed in references 9, 11, 14, 35, 37, 60, 61, and 77). Several members of the herpesvirus family, most notably herpes simplex virus type 1, inhibit autophagy within an infected cell and encode prote...

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Section: Discussionmentioning

confidence: 99%

Coxsackievirus Infection Induces Autophagy-Like Vesicles and Megaphagosomes in Pancreatic Acinar Cells In Vivo

Kemball¹,

Alirezaei²,

Flynn³

et al. 2010

J Virol

145

182

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“…Recent reports suggest that abnormalities in autophagic processing may play a role in the pathogenesis of pancreatitis (26). When the autophagy-related gene (Atg5) was genetically deleted in conditional knockout mice, trypsinogen activation was diminished and mice were protected against caerulein-induced experimental pancreatitis, suggesting that autophagic activation of trypsin may be required for the initiation of pancreatitis (9,27).…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Romac¹,

Ohmuraya

Bittner³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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RA. Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol 298: G518 -G524, 2010. First published January 28, 2010; doi:10.1152/ajpgi.00431.2009.-Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene (Spink3 Ϫ/Ϫ ) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3 Ϫ/Ϫ mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3 ϩ/Ϫ heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3 ϩ/ϩ , Spink3 ϩ/Ϫ , and Spink3 Ϫ/Ϫ /TgN(Psti1) mice had similar survival rates, no Spink3 Ϫ/Ϫ mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.PSTI-I; pancreatitis; autophagy TRYPSIN IS SYNTHESIZED in the pancreas in the form of inactive trypsinogen and stored in zymogen granules within acinar cells. Pancreatic secretory trypsin inhibitor (PSTI) is an endogenous protein inhibitor of trypsin that is also present in zymogen granules and inhibits prematurely activated trypsin to protect the pancreas from possible damage (11). Serine protease inhibitor Kazal-type 1 (SPINK1) is the human homolog of PSTI and is expressed at high levels in the pancreas (7) representing 0.1-0.6% of total pancreatic protein (8) and 0.1-0.8% of the total protein in pancreatic juice (28). It has been estimated that the amount of trypsinogen exceeds the amount of trypsin inhibitor in the pancreas, and in humans it has been shown that SPINK1 mRNA levels are 1,000-fold lower than cationic trypsinogen (PRSS1) levels (14) raising the possib...

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“…In addition, mutations in the SPINK1 gene were associated to CP. A recent study also demonstrated the role of SPINK1 as a negative regulator of autophagy in mice-deficient SPINK3 (a mouse homologue gene of human SPINK1) (47).…”

Section: Disclosurementioning

confidence: 91%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

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Genetic features of chronic pancreatitis (CP) have been investigated extensively, mainly by testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. A total of 80 patients with idiopathic chronic pancreatitis (ICP) were investigated using a Next-Generation Sequencing (NGS) approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen, modifier genes of cystic fibrosis phenotype, pancreatic secretion and ion homeostasis, calcium signaling and zymogen granules (ZG) exocytosis, autophagy and autoimmune pancreatitis-related genes. We detected mutations in 34 out of 70 genes examined; of the 80 patients, 64 (80.0%) were positive for mutations in one or more genes and 16 (20.0%) had no mutations. Mutations in CFTR were detected in 32 of the 80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38 (59.3%) of the 64 patients positive for mutations showed variants in two or more genes. Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in CP and that trans-heterozygosity may predispose to the ICP phenotype. online address: http://www.molmed.org

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Autophagy and acute pancreatitis: A novel autophagy theory for trypsinogen activation

Abstract: K. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells.

Cited by 61 publications

References 13 publications

Coxsackievirus Infection Induces Autophagy-Like Vesicles and Megaphagosomes in Pancreatic Acinar Cells In Vivo

Coxsackievirus Infection Induces Autophagy-Like Vesicles and Megaphagosomes in Pancreatic Acinar Cells In Vivo

Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

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