Functional interaction between autophagy and ciliogenesis

Pampliega, Olatz; Orhon, Idil; Patel, Bindi; Sridhar, Sunandini; Díaz-Carretero, Antonio M.; Beau, Isabelle; Codogno, Patrice; Satir, Birgit H.; Satir, Peter; Cuervo, Ana María

doi:10.1038/nature12639

Cited by 364 publications

(492 citation statements)

References 31 publications

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“…It is possible that forming autophagosomes (phagophores) have different motility than fully formed ones and changes in the fraction of phagophores with age could account for the observed differences. However, in previous studies with the LC3‐tandem reporter, we have not observed colocalization of the moving dual color vesicles with phagophore markers such as Atg5 (Bejarano et al., 2014; Pampliega et al., 2013), and consequently, we think that the resolution of our approach is not enough to detect these early forming membranes that contaminate our measurements. Whether differences in the cargo carried by autophagosomes with age could determine their different speed deserves future study.…”

Section: Discussionmentioning

confidence: 93%

“…To separately analyze autophagosome biogenesis, we next compared changes in the levels of LC3‐II at 2 and 4 hrs after inhibitor treatment (since degradation is already blocked, an increase in LC3‐II can only originate from de novo synthesis of autophagosomes; Pampliega et al., 2013). These studies revealed significantly lower rates of autophagosome formation under basal conditions in primary fibroblasts from old mice (Figure 1e,f).…”

Section: Resultsmentioning

confidence: 99%

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Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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“…9 This allows the autophagic process to control the length of the PC in response to the environmental changes. The degradation of IFT20 occurs predominantly via basal autophagy, 7 and that of OFD1 is observed early during serum starvation-induced autophagy. 9 OFD1 is encoded by the gene involved in the X-linked ciliopathy, the OFD1.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

“…5 Recent studies have shown that signals emanating from ciliated structures control the formation of autophagosomes. 7 A role for autophagy in ciliogenesis and control of cilia length has also been demonstrated. [7][8][9] The aim of this review is to present the recent findings that uncover the interplay between cilia and autophagy and to discuss their potential impact on cell homeostasis and oncilia-related disease.…”

Section: Open Questionsmentioning

confidence: 99%

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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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An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome

Tong

et al. 2017

FEBS Letters

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Human endocrine-cerebro-osteodysplasia (ECO) syndrome, caused by the loss-of-function mutation R272Q in the ICK (intestinal cell kinase) gene, is a neonatal-lethal developmental disorder. To elucidate the molecular basis of ECO syndrome, we constructed an Ick R272Q knock-in mouse model that recapitulates ECO pathological phenotypes. Newborns bearing Ick R272Q homozygous mutations die at birth due to respiratory distress. Ick mutant lungs exhibit not only impaired branching morphogenesis associated with reduced mesenchymal proliferation, but also significant airspace deficiency in primitive alveoli concomitant with abnormal interstitial mesenchymal differentiation. ICK dysfunction induces elongated primary cilia and perturbs ciliary Hedgehog signaling and autophagy during lung sacculation. Our study identifies an essential role for ICK in lung development and advances the mechanistic understanding of ECO syndrome.

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Functional interaction between autophagy and ciliogenesis

Cited by 364 publications

References 31 publications

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Autophagy and regulation of cilia function and assembly

An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome

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