Molecular mechanisms of mammalian autophagy

Abstract

The ubiquitin-proteasome pathway (UPP) and autophagy play integral roles in cellular homeostasis. As part of their normal life cycle, most proteins undergo ubiquitination for some form of redistribution, localization and/or functional modulation. However, ubiquitination is also important to the UPP and several autophagic processes. The UPP is initiated after specific lysine residues of short-lived, damaged or misfolded proteins are conjugated to ubiquitin, which targets these proteins to proteasomes. Autophagy is the endosomal/lysosomal-dependent degradation of organelles, invading microbes, zymogen granules and macromolecules such as protein, carbohydrates and lipids. Autophagy can be broadly separated into three distinct subtypes termed microautophagy, chaperone-mediated autophagy and macroautophagy. Although autophagy was once thought of as non-selective bulk degradation, advancements in the field have led to the discovery of several selective forms of autophagy. Here, we focus on the mechanisms of primary and selective mammalian autophagy pathways and highlight the current knowledge gaps in these molecular pathways.

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

“…Changes in this pathway may lead to developmental abnormalities, autoimmune diseases, neurodegenerative diseases, and cancer [27,28]. Similarly, the autophagylysosome pathway can be significantly upregulated by many cell stressors and diseases [29]. The ubiquitin-proteasome pathway is primarily responsible for degrading short-lived, soluble unfolded, and misfolded proteins.…”

“…These two proteolytic pathways are distinct in mechanism but are inextricably connected. It is reported that when the ubiquitin-proteasome pathway is inhibited or overburdened, the autophagy-lysosome pathway will be stimulated for sequestering cellular materials into autophagosomes and trafficking to lysosomes for degradation [29]. Furthermore, many proteins can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway, forming a single network for sustaining protein equilibrium [26,29].…”

“…The autophagy-lysosome pathway can be divided into several stages, including activation of autophagy initiation complexes, nucleation of phagophores, phagophore extension, autophagosome maturation, autophagosome-lysosome fusion, and lysosomal-mediated degradation [31]. Multiple protein complexes are required to manipulate autophagosome trafficking along microtubules and connect autophagosomes to lysosomes [29]. Autophagy initiation is modulated by two ser/thr kinases, the ULK1 (UNC-51-like kinase 1) and mTOR (mammalian target of rapamycin) [29].…”

microRNAs in cancer chemoresistance: The sword and the shield

“…Autophagy, a process that helps cells achieve cellular homeostasis, is characterized by the formation of autophagosomes that envelop abnormal or irregular proteins, damaged organelles, or other cytoplasmic components under stress conditions. Finally, the fusion of the autophagosome and the lysosome forms autophagolysosome where the degradation of these unwanted components occurs, which provides amino acids and other nutrients for cell growth and metabolism [ 92 ]. Cancer cells achieve chemoresistance via autophagy by 1) inhibition of autophagic cell death and 2) activation of autophagy upon stress-induced by radiotherapy and chemotherapy, causing resistance to cancer treatments [ 93 ].…”

Intestinal Macrophage Autophagy and its Pharmacological Application in Inflammatory Bowel Disease

“…After initially reported in the 1950s, the process of autophagy was systematically uncovered by Dr. Yoshinori Ohsumi, who was awarded to the 2016 Nobel Prize in Medicine or Physiology ( Rubinsztein and Frake, 2016 ; Wollert, 2019 ). So far, three kinds of classic forms of autophagy have been described, namely microautophagy, macroautophagy and chaperone-mediated autophagy ( Dash et al, 2019 ; Lin et al, 2021 ; Trelford and Di Guglielmo, 2021 ). Besides, according to the difference of degrading substrates, several kinds of selective autophagy have also been recognized and reported in various kinds of diseases, including mitophagy, pexophagy, reticulophagy, xenophagy and so on ( Kuma et al, 2017 ; Li et al, 2021 ; Xu et al, 2021 ).…”