Autophagy: cellular and molecular mechanisms

Abstract

Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease. Keywords autophagy; apoptosis; stress; mechanisms; energy; disease; cancer; neurodegeneration; infection What is autophagy?The term 'autophagy', derived from the Greek meaning 'eating of self', was first coined by Christian de Duve over 40 years ago, and was largely based on the observed degradation of mitochondria and other intra-cellular structures within lysosomes of rat liver perfused with the pancreatic hormone, glucagon [1]. The mechanism of glucagon-induced autophagy in the liver is still not fully understood at the molecular level, other than that it requires cyclic AMP induced activation of protein kinase-A and is highly tissue-specific [2]. In recent years the scientific world has 'rediscovered' autophagy, with major contributions to our molecular understanding and appreciation of the physiological significance of this process coming from numerous laboratories [3][4][5][6]. Although the importance of autophagy is well recognized in mammalian systems, many of the mechanistic breakthroughs in delineating how autophagy is regulated and executed at the molecular level have been made in yeast (Saccharomyces cerevisiae) [3, Copyright © 2010 There are three defined types of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy, all of which promote proteolytic degradation of cytosolic components at the lysosome. Macro-autophagy delivers cytoplasmic cargo to the lysosome through the intermediary of a double membrane-bound vesicle, referred to as an autophagosome, that fuses with the lysosome to form an autolysosome. In micro-autophagy, by contrast, cytosolic components are directly taken up by the lysosome itself through invagination of the lysosomal membrane. Both macro-and micro-autophagy are able to engulf large structures throu...

BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism

“…2A). The NH 4 Cl treatment results are consistent with the data obtained with BAF (Fig. 1A), which also blocks lysosomal degradation.…”

“…23,24 In order to analyze the effect of BAG3 on LC3B degradation by the lysosome, HeLa cells were treated with NH 4 Cl. This compound increases the pH of the acid organelles and inhibits the lysosomal degradation.…”

“…3 ATG4B action exposes a glycine at the carboxyl terminus of LC3B-I, which is activated by ATG7 and ATG3 and transferred to phosphatidylethanolamine to produce LC3B-II. 4 LC3B-II lies on both surfaces of autophagosome (external and internal) where it serves to elongate the membrane and recruit the cargo. In some scenarios, the induction of autophagy is accompanied by increased mRNA levels of certain autophagy genes such as LC3B, ATG5 or ATG12.…”

Why should autophagic flux be assessed?

“…Autophagy is considered to be a dynamic process that comprises three sequential steps: formation of autophagosomes, the fusion of autophagosomes with lysosomes and degradation [2] . The entrapped cargo materials within autolysosomes are degraded by hydrolases, the most important component of the cathepsin family of proteases [3] .…”

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

“…Nevertheless, once activated, AMPK27, 28, 29 and AKT29, 30 may control macroautophagy in mTORC1‐(in)dependent pathway(s). Macroautophagy, hereafter referred as to autophagy, is a multi‐step self‐degradative process by which cytoplasmic content, such as long‐lived proteins and superfluous/damaged organelles, is delivered to lysosomes for degradation 31. Deregulation of autophagy has been extensively described in AML acting both as tumour promoting and suppressing 26, 32, 33, 34.…”