Autophagy: a primer for the gastroenterologist/hepatologist

Abstract

Autophagy is a conserved cellular pathway that maintains intracellular homeostasis by degrading proteins and cytosolic contents of eukaryotic cells. Autophagy clears misfolded and long-lived proteins, damaged organelles and invading microorganisms from cells, and provides nutrients and energy in response to exposure to cell stressors such as starvation. Defective autophagy has recently been linked to a diverse range of disease processes of relevance to gastroenterologists and hepatologists including Crohn's disease, pancreatitis, hepatitis and cancer. The present article provides an overview of the autophagy pathway and discusses gastrointestinal disease processes in which alterations in autophagy have been implicated. The clinical significance of autophagy as a potential therapeutic option is also discussed.

Figure 1)

Autophagolysosome formation. On induction of autophagy, the isolation membrane or phagopore elongates and engulfs the cellular contents. Sealing of the tips leads to completion of the double-membrane autophagosome. The outer membrane then fuses with the lysosome resulting in degradation of its contents. Key elements of this process are the autophagy-related (ATG)12-ATG5-ATG16L complex, which recruits light chain (LC) 3 to the membrane, and ATG4, which controls the lipidation and recycling of LC3

Figure 2)

Autophagy regulation. Autophagy is embedded in a complex signaling network. Upstream inhibitors of autophagy include insulin and amino acids (AAs), whereas glucagon, starvation and reactive oxygen species (ROS) activate autophagy. Additional regulators of autophagy are the mammalian target of rapamycin (mTOR) and Beclin-1. The AMP-activated protein kinase (AMPK) senses energy deprivation and enhances autophagy via mTOR inhibition. The main pharmacological mTOR inhibitor is rapamycin. Beclin-1 and ultaviolet radiation resistance-associated gene protein (UVRAG) activate autophagy, whereas binding of the anti-apoptotic Bcl-2/Bcl-Xl to Beclin-1 leads to inhibition of autophagy. The class III phosphatidylinositol-3-kinase (PI3K) regulates autophagy in concert with Beclin-1 and can be blocked by the pharmacological agent 3-methyladenine (3MA), thereby blocking autophagy. Both the tumour suppressor protein p53 and Bcl-2/Bcl-Xl connect autophagy with apoptosis

Figure 3)

Autophagy in Crohn’s disease. A Paneth cells with the autophagy-related (ATG)16L risk allele show structural and functional abnormalities. They exhibit disorganized and diminished lysozyme granules and degraded mitochondria resulting in reduced lysozymes in the mucosal layer potentially causing bacterial overgrowth. B Nucleotide-binding oligomerization domain containing 2 (NOD2) senses bacterial muramyl dipeptide (MDP) and recruits ATG16L to the cellular membrane to initiate autophagy of intracellular bacteria. Mutant NOD2L1007insC has reduced autophagy in response to MDP. Additionally, the NOD2-supported antigen presentation via major histocompatibility complex class II (MHC II) in dendritic cells with the risk alleles is defective and results in impaired activation of CD4 T cells. C Immunity-related GTPase family, M (IRGM) activates autophagy for xenophagy. The Crohn’s disease risk allele IRGM C313T messenger RNA lacks the binding site for microRNA (miRNA)-196, leading to upregulation of IRGM, which results in decreased efficacy of autophagy and increased intracellular bacterial survival

Figure 4)

Autophagy in pancreatitis. Autophagy is induced during pancreatitis, but the degradation of autolysosomes is impaired with accumulation of large vacuoles. Reduced activity of the lysosomal cathepsins (Cat) L and B was detected in autophagosomes, with Cat L more greatly affected than Cat B. The imbalance between the lysosomal hydrolases Cat B and Cat L increases the intra-acinar trypsin leading to cell necrosis and inflammation

Figure 5)

Autophagy in alpha-1-antitrypsin (A1AT) deficiency. The misfolded mutant A1AT forms polymers that accumulate in the endoplasmatic reticulum (ER), which causes ER stress and inflammation. Monomers can be degraded in proteasomes whereas polymer degradation takes place in autophagolysosomes. Enhancing autophagy with carbamazepine increases the disposal of mutant A1AT and subsequently ameliorates its hepatotoxicity