title: Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways.
abstract: 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. It was found that autophagy was repressed in cells with short cilia. Further investigation showed that MTOR activation was enhanced in cilia-suppressed cells and the MTOR inhibitor rapamycin could largely reverse autophagy suppression. In human kidney proximal tubular cells (HK2), autophagy induction was associated with cilium elongation. Conversely, autophagy inhibition by 3-methyladenine (3-MA) and chloroquine (CQ) as well as bafilomycin A1 (Baf) led to short cilia. Cilia were also shorter in cultured atg5-knockout (KO) cells and in atg7-KO kidney proximal tubular cells in mice. MG132, an inhibitor of the proteasome, could significantly restore cilium length in atg5-KO cells, being concomitant with the proteasome activity. Together, the results suggest that cilia and autophagy regulate reciprocally through the MTOR signaling pathway and ubiquitin-proteasome system.
authors.affiliation: a Department of Cellular Biology and Anatomy ; Medical College of Georgia; Georgia Reagents University and Charlie Norwood VA Medical Center ; Augusta , GA USA.
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Man J
authors.initials: MJ
authors.lastname: Livingston
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Su
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002923:Cilia / Q000235:genetics; D006801:Humans; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: 3-MA, 3-methyladenine; 70kDa, polypeptide 1; ANKS6, ankyrin repeat and sterile α motif domain containing 6; ATG/atg, autophagy-related; Ac-TUBA, acetylated-tubulin α; Baf, bafilomycin A1; CF, confluence; CQ, chloroquine; DAPI, 4′-6-diamidino-2-phenylindole; FBS, fetal bovine serum; HK2, human kidney proximal tubular cells; IFT, intraflagellar transport; KAP3, kinesin family-associated protein 3; KD, knockdown; KIF3A/3B, kinesin family member 3A/3B; KO, knockout; LTA, lotus tetragonolobus agglutinin; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 β; MEF, mouse embryonic fibroblast; MTOR; MTOR, mechanistic target of rapamycin; OFD1, oral-ficial-digital syndrome 1; PBS, phosphate-buffered saline; PKD, polycystic kidney disease; RKRB, Krebs-Henseleit saline containing 25 mM NaHCO3; RPS6KB1, ribosomal protein S6 kinase; Rapa, rapamycin; SD, standard deviation; autophagy; cilia; polycystic kidney disease; proteasome