To achieve homeostasis, cells evolved dynamic and self-regulating quality control processes to adapt to new environmental conditions and to prevent prolonged damage. We discuss the importance of two ...major quality control systems responsible for degradation of proteins and organelles in eukaryotic cells: the ubiquitin-proteasome system (UPS) and autophagy. The UPS and autophagy form an interconnected quality control network where decision-making is self-organized on the basis of biophysical parameters (binding affinities, local concentrations, and avidity) and compartmentalization (through membranes, liquid-liquid phase separation, or the formation of aggregates). We highlight cellular quality control factors that delineate their differential deployment toward macromolecular complexes, liquid-liquid phase-separated subcellular structures, or membrane-bound organelles. Finally, we emphasize the need for continuous promotion of quantitative and mechanistic research into the roles of the UPS and autophagy in human pathophysiology.
The endoplasmic reticulum (ER) is one of the most complex organelles in the eukaryotic cell. Recent findings suggest that a process called ER-phagy plays a major role in maintaining the ER's shape ...and function.
Autophagy is a highly conserved catabolic process cells use to maintain their homeostasis by degrading misfolded, damaged and excessive proteins, nonfunctional organelles, foreign pathogens and other ...cellular components. Hence, autophagy can be nonselective, where bulky portions of the cytoplasm are degraded upon stress, or a highly selective process, where preselected cellular components are degraded. To distinguish between different cellular components, autophagy employs selective autophagy receptors, which will link the cargo to the autophagy machinery, thereby sequestering it in the autophagosome for its subsequent degradation in the lysosome. Autophagy receptors undergo post‐translational and structural modifications to fulfil their role in autophagy, or upon executing their role, for their own degradation. We highlight the four most prominent protein modifications – phosphorylation, ubiquitination, acetylation and oligomerisation – that are essential for autophagy receptor recruitment, function and turnover. Understanding the regulation of selective autophagy receptors will provide deeper insights into the pathway and open up potential therapeutic avenues.
Selective autophagy receptors are essential for bridging the cellular cargo destined for degradation with autophagy machinery. As such, their role in autophagy is strictly regulated. In this review, we outline and discuss post‐translational (phosphorylation, ubiquitination, acetylation) and structural (oligomerisation) modifications involved in regulating the function of cargo receptors in selective autophagy, and highlight the importance of it in maintaining cellular fitness and homeostasis.
Efficacy and selectivity of molecules inducing protein degradation depend on their affinity to the target protein but also on the type of E3 ubiquitin ligase that is recruited to trigger proteasomal ...degradation. While tremendous progress has been made on the former, the latter—the arsenal of E3 ligases that can be hijacked for targeted protein degradation—is still largely unexplored. Only about 2% of the more than 600 E3 ligases have been utilized to date. Exploiting additional E3 ligases that are, for example, selectively expressed in specific tissues or cells, or regulated under certain conditions, can considerably broaden the applicability of molecular degraders as a therapeutic modality. Here, we provide an overview of major classes of E3 ligases, review the enzymes that have been exploited for induced protein degradation and approaches used to identify or design E3 ligands, and highlight challenges and opportunities for targeting new E3 ligases.
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Kannt and Đikić give an overview of E3 ubiquitin ligases that have been utilized for induced protein degradation. They outline challenges and opportunities related to targeting additional E3 ligases and summarize approaches and recent technological advances to identify and design new ligands and repurpose E3 ligases for targeted protein degradation.
Ubiquitin acts as a versatile cellular signal that controls a wide range of biological processes including protein degradation, DNA repair, endocytosis, autophagy, transcription, immunity, and ...inflammation. The specificity of ubiquitin signaling is achieved by alternative conjugation signals (monoubiquitin and ubiquitin chains) and interactions with ubiquitin-binding proteins (known as ubiquitin receptors) that decode ubiquitinated target signals into biochemical cascades in the cell. Herein, we review the current knowledge pertaining to the structural and functional features of ubiquitin-binding proteins and the mechanisms by which they recognize various types of ubiquitin topologies. The combinatorial use of diverse ubiquitin-binding domains (UBDs) in full-length proteins, selective recognition of chains with distinct linkages and length, and posttranslational modifications of ubiquitin receptors or multivalent interactions within protein complexes illustrate a few mechanisms by which a circuitry of signaling networks can be rewired by ubiquitin-binding proteins to control cellular functions in vivo.
Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process ...requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways.
Ubiquitylation is among the most prevalent post‐translational modifications (PTMs) and regulates numerous cellular functions. Interestingly, ubiquitin (Ub) can be itself modified by other PTMs, ...including acetylation and phosphorylation. Acetylation of Ub on K6 and K48 represses the formation and elongation of Ub chains. Phosphorylation of Ub happens on multiple sites, S57 and S65 being the most frequently modified in yeast and mammalian cells, respectively. In mammals, the PINK1 kinase activates ubiquitin ligase Parkin by phosphorylating S65 of Ub and of the Parkin Ubl domain, which in turn promotes the amplification of autophagy signals necessary for the removal of damaged mitochondria. Similarly, TBK1 phosphorylates the autophagy receptors OPTN and p62 to initiate feedback and feedforward programs for Ub‐dependent removal of protein aggregates, mitochondria and pathogens (such as Salmonella and Mycobacterium tuberculosis). The impact of PINK1‐mediated phosphorylation of Ub and TBK1‐dependent phosphorylation of autophagy receptors (OPTN and p62) has been recently linked to the development of Parkinson's disease and amyotrophic lateral sclerosis, respectively. Hence, the post‐translational modification of Ub and its receptors can efficiently expand the Ub code and modulate its functions in health and disease.
This Review analyzes how phosphorylation, acetylation and deamidation of ubiquitin can regulate its functions, focusing on the role of ubiquitin phosphorylation in the control of selective autophagy pathways.
Ubiquitin chain diversity at a glance Akutsu, Masato; Dikic, Ivan; Bremm, Anja
Journal of cell science,
03/2016, Volume:
129, Issue:
5
Journal Article
Peer reviewed
Open access
Ubiquitin plays an essential role in modulating protein functions, and deregulation of the ubiquitin system leads to the development of multiple human diseases. Owing to its molecular features, ...ubiquitin can form various homo- and heterotypic polymers on substrate proteins, thereby provoking distinct cellular responses. The concept of multifaceted ubiquitin chains encoding different functions has been substantiated in recent years. It has been established that all possible ubiquitin linkage types are utilized for chain assembly and propagation of specific signals in vivo. In addition, branched ubiquitin chains and phosphorylated ubiquitin molecules have been put under the spotlight recently. The development of novel technologies has provided detailed insights into the structure and function of previously poorly understood ubiquitin signals. In this Cell Science at a Glance article and accompanying poster, we provide an update on the complexity of ubiquitin chains and their physiological relevance.
Ligand-induced activation of transmembrane receptors activates intracellular signaling cascades that control vital cellular processes, such as cell proliferation, differentiation, migration and ...survival. Receptor signaling is modulated by several mechanisms to ensure that the correct biological outcome is achieved. One such mechanism, which negatively regulates receptor signaling, involves the modification of receptors with ubiquitin. This post-translational modification can promote receptor endocytosis and targets receptors for lysosomal degradation, thereby ensuring termination of receptor signaling. In this Commentary, we review the roles of ubiquitylation in receptor endocytosis and degradative endosomal sorting by drawing on the epidermal growth factor receptor (EGFR) as a well-studied example. Furthermore, we elaborate on the molecular basis of ubiquitin recognition along the endocytic pathway through compartment-specific ubiquitin-binding proteins and highlight how endocytic sorting machineries control these processes. In addition, we discuss the importance of ubiquitin-dependent receptor endocytosis for the maintenance of cellular homeostasis and in the prevention of diseases such as cancer.
Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence ...their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection. In this review, we summarize how different bacteria and viruses impact morphological and functional changes in host mitochondria and how this manipulation can influence microbial pathogenesis as well as the host cell metabolism and immune responses.
Bacteria and viruses have evolved specific ways of targeting mitochondria to perturb mitochondrial function that can prove to be beneficial for these microbes.Many bacteria and viruses use specific virulence mechanisms to modulate mitochondrial dynamics, leading to either mitochondrial fusion or fission.Mitochondrial metabolism can also be impacted by bacterial and viral infections.While in some cases bacteria and viruses induce the mitochondrial cell death pathway, in others cell death is inhibited promoting intracellular bacterial and viral proliferation.Mitochondria regulate different innate immune signaling pathways induced upon bacterial or viral infections.
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