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Cilia and autophagy

Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E Teves, Hong Liu, Jerome F Strauss, Gregory J Pazour, James A Foster, Rex A Hess, Zhibing Zhang
Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules...
September 28, 2016: Molecular Biology of the Cell
Birgit Hegner Satir, Olatz Pampliega
Autophagy is a catabolic pathway for the degradation and recycling of intracellular components, contributing to maintain cell homeostasis. Changes in autophagy activity can be monitored by a variety of biochemical and functional assays that should be used in combination. Recently, it has been described that signaling from the primary cilium modulates autophagy. This novel and reciprocal interaction will impact diverse aspects of the cell biology in healthy and pathophysiological conditions. Here, we describe methods to monitor autophagy activity in cilia mutants, as well as the use of autophagy mutants to monitor ciliogenesis...
2016: Methods in Molecular Biology
Qian Xu, Wei Liu, Xiaoling Liu, Weiwei Liu, Hongju Wang, Guodong Yao, Linghe Zang, Toshihiko Hayashi, Shin-Ichi Tashiro, Satoshi Onodera, Takashi Ikejima
Primary cilium is a cellular antenna, signalling as a sensory organelle. Numerous pathological manifestation is associated with change of its length. Although the interaction between autophagy and primary cilia has been suggested, the role of autophagy in primary cilia length is largely unknown. In this study the primary cilia were immunostained and observed by using confocal fluorescence microscopy, and we found that silibinin, a natural flavonoid, shortened the length of primary cilia, meanwhile it also induced autophagy in 3T3-L1 cells...
September 2016: Molecular and Cellular Biochemistry
Zsuzsanna Takacs, Tassula Proikas-Cezanne
The primary cilium and the process of autophagy are thought to be in a functionally reciprocal relationship. In further support of this link, fluid flow sensing by the primary cilium is now shown to induce autophagy, which in turn regulates the volume of kidney epithelial cells.
May 27, 2016: Nature Cell Biology
Katie L Bales, Alecia K Gross
Retinal trafficking proteins are involved in molecular assemblies that govern protein transport, orchestrate cellular events involved in cilia formation, regulate signal transduction, autophagy and endocytic trafficking, all of which if not properly controlled initiate retinal degeneration. Improper function and or trafficking of these proteins and molecular networks they are involved in cause a detrimental cascade of neural retinal remodeling due to cell death, resulting as devastating blinding diseases. A universal finding in retinal degenerative diseases is the profound detection of retinal remodeling, occurring as a phased modification of neural retinal function and structure, which begins at the molecular level...
September 2016: Experimental Eye Research
M Kaliszewski, A B Knott, E Bossy-Wetzel
Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology...
September 2015: Cell Death and Differentiation
Ji Hyun Shin, Dong-Jun Bae, Eun Sung Kim, Han Byeol Kim, So Jung Park, Yoon Kyung Jo, Doo Sin Jo, Dong-Gyu Jo, Sang-Yeob Kim, Dong-Hyung Cho
Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium...
July 2015: Biomolecules & Therapeutics
Guoxiang Jin, Szu-Wei Lee, Xian Zhang, Zhen Cai, Yuan Gao, Ping-Chieh Chou, Abdol Hossein Rezaeian, Fei Han, Chi-Yun Wang, Juo-Chin Yao, Zhaohui Gong, Chia-Hsin Chan, Chih-Yang Huang, Fuu-Jen Tsai, Chang-Hai Tsai, Shih-Hsin Tu, Chih-Hsiung Wu, Dos D Sarbassov, Yuan-Soon Ho, Hui-Kuan Lin
The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation...
June 18, 2015: Molecular Cell
Shixuan Wang, Man J Livingston, Yunchao Su, Zheng Dong
Primary cilium is an organelle that plays significant roles in a number of cellular functions ranging from cell mechanosensation, proliferation, and differentiation to apoptosis. Autophagy is an evolutionarily conserved cellular function in biology and indispensable for cellular homeostasis. Both cilia and autophagy have been linked to different types of genetic and acquired human diseases. Their interaction has been suggested very recently, but the underlying mechanisms are still not fully understood. We examined autophagy in cells with suppressed cilia and measured cilium length in autophagy-activated or -suppressed cells...
April 3, 2015: Autophagy
Ji Hyun Shin, Pan Soo Kim, Eun Sung Kim, So Jung Park, Yoon Kyung Jo, Jung Jin Hwang, Tae Joo Park, Jong Wook Chang, Jin-Ho Seo, Dong-Hyung Cho
Previously, we showed that BIX-01294 treatment strongly activates autophagy. Although, the interplay between autophagy and ciliogenesis has been suggested, the role of autophagy in ciliogenesis is controversial and largely unknown. In this study, we investigated the effects of autophagy induced by BIX-01294 on the formation of primary cilia in human retinal pigmented epithelial (RPE) cells. Treatment of RPE cells with BIX-01294 caused strong elongation of the primary cilium and increased the number of ciliated cells, as well as autophagy activation...
May 1, 2015: Biochemical and Biophysical Research Communications
Eun Sung Kim, Ji Hyun Shin, So Jung Park, Yoon Kyung Jo, Jae-Sung Kim, Il-Hwan Kang, Jung-Bum Nam, Doo-Young Chung, Yoonchul Cho, EunJoo H Lee, Jong Wook Chang, Dong-Hyung Cho
Primary cilia are conserved cellular organelles that regulate diverse signaling pathways. Autophagy is a complex process of cellular degradation and recycling of cytoplasmic proteins and organelles, and plays an important role in cellular homeostasis. Despite its potential importance, the role of autophagy in ciliogenesis is largely unknown. In this study, we identified sertraline as a regulator of autophagy and ciliogenesis. Sertraline, a known antidepressant, induced the growth of cilia and blocked the disassembly of cilia in htRPE cells...
2015: PloS One
Stefan W Ryter, Augustine M K Choi
Autophagy, a cellular pathway for the degradation of damaged organelles and proteins, has gained increasing importance in human pulmonary diseases, both as a modulator of pathogenesis and as a potential therapeutic target. In this pathway, cytosolic cargos are sequestered into autophagosomes, which are delivered to the lysosomes where they are enzymatically degraded and then recycled as metabolic precursors. Autophagy exerts an important effector function in the regulation of inflammation, and immune system functions...
2015: Redox Biology
Kenji Mizumura, Augustine M K Choi, Stefan W Ryter
Autophagy was originally described as a highly conserved system for the degradation of cytosol through a lysosome-dependent pathway. In response to starvation, autophagy degrades organelles and proteins to provide metabolites and energy for its pro-survival effects. Autophagy is recognized as playing a role in the pathogenesis of disease either directly or indirectly, through the regulation of vital processes such as programmed cell death, inflammation, and adaptive immune mechanisms. Recent studies have demonstrated that autophagy is not only a simple metabolite recycling system, but also has the ability to degrade specific cellular targets, such as mitochondria, cilia, and invading bacteria...
2014: Frontiers in Pharmacology
I Orhon, N Dupont, O Pampliega, A M Cuervo, P Codogno
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...
March 2015: Cell Death and Differentiation
Peter Satir
This essay records a voyage of discovery from the "cradle of cell biology" to the present, focused on the biology of the oldest known cell organelle, the cilium. In the "romper room" of cilia and microtubule (MT) biology, the sliding MT hypothesis of ciliary motility was born. From the "summer of love," students and colleagues joined the journey to test switch-point mechanisms of motility. In the new century, interest in nonmotile (primary) cilia, never lost from the cradle, was rekindled, leading to discoveries relating ciliogenesis to autophagy and hypotheses of how molecules cross ciliary necklace barriers for cell signaling...
November 1, 2014: Molecular Biology of the Cell
Kameswaran Ravichandran, Charles L Edelstein
Autosomal-dominant polycystic kidney disease is the most common form of polycystic kidney disease in adults and is caused by a mutation in the polycystic kidney disease 1 or 2 genes, which encode, respectively, polycystin-1 and polycystin-2. Autophagy is present in polycystic kidneys in rat and mouse models of polycystic kidney disease. Autophagy has yet to be shown in human polycystic kidney disease kidneys. The mechanism of cyst growth has been studied extensively in vitro and in vivo. Multiple molecules and signaling pathways have been implicated in cyst growth including mammalian target of rapamycin, the renin-angiotensin-aldosterone system, vasopressin and cyclic adenosine monophosphate, epidermal growth factor and insulin-like growth factor tyrosine kinases, vascular endothelial growth factor, extracellular signal-related kinase, tumor necrosis factor-α, cyclin-dependent kinases, caspases and apoptosis, and cyclic adenosine monophosphate-activated protein kinases...
January 2014: Seminars in Nephrology
Suzanne M Cloonan, Hilaire C Lam, Stefan W Ryter, Augustine M Choi
Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated...
March 2014: Autophagy
Ashley A George, Sara Hayden, Lars C Holzhausen, Eva Y Ma, Sachihiro C Suzuki, Susan E Brockerhoff
Highly polarized cells such as photoreceptors require precise and efficient strategies for establishing and maintaining the proper subcellular distribution of proteins. The signals and molecular machinery that regulate trafficking and sorting of synaptic proteins within cone inner segments is mostly unknown. In this study, we show that the polyphosphoinositide phosphatase Synaptojanin 1 (SynJ1) is critical for this process. We used transgenic markers for trafficking pathways, electron microscopy, and immunocytochemistry to characterize trafficking defects in cones of the zebrafish mutant, nrc(a14) , which is deficient in phosphoinositide phosphatase, SynJ1...
2014: PloS One
Zaiming Tang, Muyuan Zhu, Qing Zhong
Autophagy delivers many proteins and cellular components to the lysosome for degradation via selective or nonselective mechanisms. By controlling the stability of defined protein factors, autophagy might regulate cellular processes in a precise and finely-tuned manner. In this study, we demonstrated that autophagy positively regulates the biogenesis of the primary cilium, an antenna-like organelle that senses the environment and transduces signals. Defects in the function or structure of cilia cause a number of human diseases called "ciliopathies...
February 2014: Autophagy
Hilaire C Lam, Suzanne M Cloonan, Abhiram R Bhashyam, Jeffery A Haspel, Anju Singh, J Fah Sathirapongsasuti, Morgan Cervo, Hongwei Yao, Anna L Chung, Kenji Mizumura, Chang Hyeok An, Bin Shan, Jonathan M Franks, Kathleen J Haley, Caroline A Owen, Yohannes Tesfaigzi, George R Washko, John Quackenbush, Edwin K Silverman, Irfan Rahman, Hong Pyo Kim, Ashfaq Mahmood, Shyam S Biswal, Stefan W Ryter, Augustine M K Choi
Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/- or Map1lc3B-/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis...
December 2013: Journal of Clinical Investigation
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