Autophagy and regulation of cilia function and assembly

Abstract

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...

Autophagy in renal diseases

“…The latter are the solitary, microtubule-based, non-motile structures growing from the centriole and protruding from the plasma membrane of many cell types, sensing and transducing input from the extracellular environment (mechanical stress, nutrients, growth factors, and Ca 2+ changes) into different cellular signalling pathways [40]. The fact that nutrient deprivation is a primary stimulus shared by both autophagy and primary cilia formation supports the proposed relationship between the two processes [41].…”

“…These findings show that autophagy must be considered as a factor in the development of conditions associated with defective cilia, called ciliopathies, such as autosomal dominant polycystic kidney disease (ADPKD) [6,41]. Mutations in various ciliary proteins, including IFT88 and IFT20, can result in cyst formation [40]. ADPKD is characterised by a disturbance in many signalling pathways, several of which are directly related to the regulation of autophagy, e.g., mTOR signalling and intracellular Ca 2+ signalling [44][45][46].…”

“…These proteins are involved in cellular repair and growth mechanisms. Epithelial cyst-lining cells expressing mutated PC1 display higher rates of cell proliferation [40]. However, their exact role is complex and not fully clarified [40].…”

“…Epithelial cyst-lining cells expressing mutated PC1 display higher rates of cell proliferation [40]. However, their exact role is complex and not fully clarified [40]. Extensive study of the mechanism of cyst development and growth, in vitro and in vivo, has shown that multiple molecular parameters and signalling pathways are involved, such as mTOR, vasopressin, cyclic adenosine monophosphate, several growth factors, caspases, and apoptosis [41].…”

“…This includes both components essential for ciliogenesis, such as IFT20, and negative ciliogenesis regulators, such as oral facial digital syndrome 1 (OFD1), depending upon experimental conditions [40]. Atg5-null cells, which are defective in autophagy, formed cilia at a faster rate and of longer length than wild-type cells [42].…”