Interactions between Autophagy Receptors and Ubiquitin-like Proteins Form the Molecular Basis for Selective Autophagy

Rogov, Vladimir V.; Dötsch, Volker; Johansen, Terje; Kirkin, Vladimir

doi:10.1016/j.molcel.2013.12.014

Cited by 894 publications

(863 citation statements)

References 84 publications

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“…This protein is incorporated into mature autophagosomes and degraded in autolysosomes, serving as a readout of the autophagic pathway. 29 The distribution of SQSTM1/p62 puncta perfectly matches that of LC3 puncta ( Supplementary Figures S1c and d). Its transcriptional upregulation in Pat#1 fibroblasts further demonstrates that 13514A4G cells have an increased autophagosome formation rather than a block in their degradation (Figure 1d).…”

Section: Resultssupporting

confidence: 58%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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Section: Resultssupporting

confidence: 58%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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“…As a result, autophagy cargo receptors act as molecular bridges that capture ubiquitylated proteins targeted for degradation by the autophagy pathway and complement the UPS. For example, the autophagy cargo receptors p62 (also known as SQSTM1), NBR1 (next to BRCA1 gene 1 protein) and histone deacetylase 6 (HDAC6) all promote the autophagic clearance of protein aggregates in a process known as aggrephagy, which is dependent on both the UBD and LIR 2,10 . In yeast, although orthologues of UBD-containing adaptor proteins such as p62 are missing, a recent mass spectrometric study identified Cue5 as a potential autophagy cargo receptor 23 .…”

Section: Overview Of the Autophagic Pathwaymentioning

confidence: 99%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

842

801

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“…50 Although in general autophagy is an in bulk process, it can also be highly selective toward cellular structures and microorganisms invading the cytoplasm. The paradigm for selective autophagy is the recognition of the cargo by autophagy receptors (p62/SQSTM1, NBR1, NDP52, optineurin and BNIP3L), which connect the cargo to the autophagy machinery (reviewed in references Birgisdottir et al 51 ; Okamoto 52 ; Rogov et al 53 ; and Stolz et al 54 ).…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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Interactions between Autophagy Receptors and Ubiquitin-like Proteins Form the Molecular Basis for Selective Autophagy

Cited by 894 publications

References 84 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Autophagy at the crossroads of catabolism and anabolism

Autophagy and regulation of cilia function and assembly

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