SummaryNutrient deprivation is a stimulus shared by both autophagy and the formation of primary cilia. The recently discovered role of primary cilia in nutrient sensing and signaling motivated us to explore the possible functional interactions between this signaling hub and autophagy. Here we show that part of the molecular machinery involved in ciliogenesis also participates in the early steps of the autophagic process. Signaling from the cilia, such as that from the Hedgehog pathway, induces autophagy by acting directly on essential autophagy-related proteins strategically located in the base of the cilium by ciliary trafficking proteins. While abrogation of ciliogenesis partially inhibits autophagy, blockage of autophagy enhances primary cilia growth and cilia-associated signaling during normal nutritional conditions. We propose that basal autophagy regulates ciliary growth through the degradation of proteins required for intraflagellar transport. Compromised ability to activate the autophagic response may underlie the basis of some common ciliopathies.

Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, the intensive scrutiny that autophagy has been subjected to at the molecular level, has also contributed to expand our understanding of the physiological role of this pathway. Added to the well-characterized role in quality control, autophagy has proven important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodeling and in the cellular defense against extracellular insults and pathogens. It is not a surprise that in light of this growing number of physiological functions, connections between autophagic malfunctioning and human pathologies have also been strengthened. In this review, we focus on several pathological conditions associated to primary or secondary defects in autophagy, and comment on a recurring theme for many of them, that is the fact that autophagy can often exert both beneficial and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between these dual functions of autophagy in disease has become a priority when considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions.

Summary Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of cytosolic proteins in lysosomes that contributes to cellular quality control and becomes an additional source of amino acids when nutrients are scarce. A chaperone complex delivers CMA substrates to a receptor protein at the lysosomal membrane that assembles into multimeric translocation complexes. However, the mechanisms regulating this process remain, for the most part, unknown. In this work, we have identified two regulatory proteins, GFAP and EF1α, that mediate a previously unknown inhibitory effect of GTP on CMA. GFAP stabilizes the multimeric translocation complex against chaperone-mediated disassembly, whereas GTP-mediated release of EF1α from the lysosomal membrane promotes self-association of GFAP, disassembly of the CMA translocation complex and the consequent decrease in CMA. The dynamic interactions of these two proteins at the lysosomal membrane unveil now a role for GTP as negative regulator of CMA.

Chaperone-mediated autophagy (CMA) is an intracellular catabolic pathway that mediates the degradation of a selective subset of cytosolic proteins in lysosomes (Dice, 2007;Cuervo, 2010;Kon and Cuervo, 2010;Orenstein and Cuervo, 2010). The term autophagy (or selfeating) is broadly used to designate the lysosomal delivery and degradation of intracellular components (Mizushima et al., 2008;Mizushima and Levine, 2010;Yang and Klionsky, 2010). Various types of autophagy coexist in almost all cells, and they can be differentiated by the mechanisms that mediate the delivery of cargo (the substrates to be degraded) to lysosomes. Macroautophagy and microautophagy are variants of the autophagic process, in which entire regions of cytosol (in 'bulk' autophagy) or selective cytosolic components (organelles, protein complexes, protein aggregates, pathogens, etc.) are sequestered in vesicular compartments. Lysosomal enzymes can gain access to the enclosed cargo through direct fusion of the vesicles with lysosomes (in macroautophagy), or by internalization of cargo-containing vesicles that form at the lysosomal membrane (in microautophagy). A third form of autophagy, solely dedicated to degradation of soluble proteins can also be detected in most cell types in mammals. This autophagic process, known as chaperone-mediated autophagy, differs from the other forms of autophagy in both the way in which cargo proteins are recognized for lysosomal delivery and the way in which these proteins reach the lysosomal lumen (Dice, 2007;Cuervo, 2010). In this article and the accompanying poster, we summarize the main steps involved in degradation of cytosolic proteins by CMA, the essential components of this pathway both in the cytosol and at the lysosomal membrane and the basis for the regulation of this autophagic process. We also include a synopsis of the described physiological functions of CMA and some (See poster insert) Degradation by the lysosomal proteases CMA is a selective form of autophagy by which single soluble proteins are directed one-by-one to lysosomes for degradation.The steps in CMA are:Validated CMA substrates

Lipid modifications are essential in cellular sorting and trafficking inside cells. The role of phosphoinositides in trafficking between Golgi and endocytic/lysosomal compartments has been extensively explored and the kinases responsible for these lipid changes have been identified. In contrast, the mechanisms that mediate exit and recycling from lysosomes (Lys), considered for a long time as terminal compartments, are less understood. In this work, we identify a dynamic association of the lipid kinase PI4KIIIβ with Lys and unveil its regulatory function in lysosomal export and retrieval. We have found that absence of PI4KIIIβ leads to abnormal formation of tubular structures from the lysosomal surface and loss of lysosomal constituents through these tubules. We demonstrate that the kinase activity of PI4KIIIβ is necessary to prevent this unwanted lysosomal efflux under normal conditions, and to facilitate proper sorting when recycling of lysosomal material is needed, such as in the physiological context of lysosomal reformation after prolonged starvation.