Non-Motile Primary Cilia as Fluid Shear Stress Mechanosensors

Nauli, Surya M.; Jin, Xingjian; AbouAlaiwi, Wissam A.; El-Jouni, Wassim; Su, Xiaoqiang; Zhou, Jing

doi:10.1016/b978-0-12-397944-5.00001-8

Cited by 56 publications

(52 citation statements)

References 53 publications

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“…12,44, 45 We speculate that shortening of cilia induced by autophagy suppression changes the cilia-sensing ability, and subsequently sensitizes cells to injury and apoptosis as found recently. 23 Based upon the fact that some proteins such as IFT20 are found in both secretory vesicles and the primary cilia 46 as well as in the urine exosomes, 47 it has been suggested that a large number of substances may be excreted from the ciliary membrane through exocytosis or bud-off at the tip.…”

Section: Discussionsupporting

confidence: 55%

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Wang¹,

Livingston

et al. 2015

Autophagy

117

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Abbreviations: 3-MA, 3-methyladenine; ANKS6, ankyrin repeat and sterile a motif domain containing 6; ATG/atg, autophagy-related; Baf, bafilomycin A 1 ; DAPI, 4 0 -6-diamidino-2-phenylindole; Ac-TUBA, acetylated-tubulin a; CQ, chloroquine; CF, confluence; FBS, fetal bovine serum; HK2, human kidney proximal tubular cells; IFT, intraflagellar transport; K D , knockdown; KAP3, kinesin family-associated protein 3; KIF3A/3B, kinesin family member 3A/3B; KO, knockout; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; LTA, lotus tetragonolobus agglutinin; MEF, mouse embryonic fibroblast; MTOR, mechanistic target of rapamycin; OFD1, oral-ficial-digital syndrome 1; PBS, phosphate-buffered saline; PKD, polycystic kidney disease; Rapa, rapamycin; RKRB, Krebs-Henseleit saline containing 25 mM NaHCO 3 ; RPS6KB1, ribosomal protein S6 kinase; 70kDa, polypeptide 1; SD, standard deviation.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 A 1 (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.

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Section: Discussionsupporting

confidence: 55%

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Wang¹,

Livingston

et al. 2015

Autophagy

117

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“…Primary cilia are solitary rigid structures that extend from the cell body into the extracellular space and are more likely to be the "antennae" to receive or sense the signals from extracellular environment. It has been shown that, during extracellular fluid flow, primary cilia deflect on osteocytes (the major type of bone cells that regulate bone remodeling), and that these primary cilia are required for the osteocytes to trigger an osteogenic or bone resorptive signal to their surroundings in response to dynamic fluid flow (Delaine-Smith et al, 2004;Malone et al, 2007;Nauli et al, 2013). Furthermore, it has been proposed that NO/ cGMP signaling has a strong ciliary basis (Johnson and Leroux, 2010), which may explain the involvement of Ca 2+ /NO/cGMP/PKG pathway in EMF action.…”

Section: Discussionmentioning

confidence: 99%

Pulsed electromagnetic fields promote osteoblast mineralization and maturation needing the existence of primary cilia

Yan

Zhou

et al. 2015

Molecular and Cellular Endocrinology

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Although pulsed electromagnetic fields (PEMFs) have been approved as a therapy for osteoporosis, action mechanisms and optimal parameters are elusive. To determine the optimal intensity, exposure effects of 50 Hz PEMFs of 0.6-3.6 mT (0.6 interval at 90 min/day) were investigated on proliferation and osteogenic differentiation of cultured calvarial osteoblasts. All intensity groups stimulated proliferation significantly with the highest effect at 0.6 mT. The 0.6 mT group also obtained the optimal osteogenic effect as demonstrated by the highest ALP activity, ALP(+) CFU-f colony formation, nodule mineralization, and expression of COL-1 and BMP-2. To verify our hypothesis that the primary cilia are the cellular sensors for PEMFs, osteoblasts were also transfected with IFT88 siRNA or scrambled control, and osteogenesis-promoting effects of 0.6 mT PEMFs were found abrogated when primary cilia were inhibited by IFT88 siRNA. Thus primary cilia of osteoblasts play an indispensable role in mediating PEMF osteogenic effect in vitro.

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“…Studies of mammalian polycystins expressed heterologously in cells such as Xenopus oocytes, CHO cells, HEK cells, and cultured sympathetic neurons have uncovered many functions of the polycystins [7, 29, 46]. The functions demonstrated in these systems are often in conflict with one another, possibly reflecting the different cellular environments of each expression system [29].…”

Section: Functions Of Polycystinsmentioning

confidence: 99%

“…Internal sensing includes reception of signaling from nearby cells [3] as well as other stimuli. For example, cilia that protrude from kidney epithelia are proposed to sense urine flow through the kidneys [6, 7]. Loss of the ability to sense urine flow is proposed to lead to polycystic kidney disease [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Mating behavior, male sensory cilia, and polycystins in Caenorhabditis elegans

O’Hagan

Wang

Barr

2014

Seminars in Cell & Developmental Biology

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The investigation of C. elegans males and the male-specific sensory neurons required for mating behaviors has provided insight into the molecular function of polycystins and mechanisms that are needed for polycystin ciliary localization. In humans, polycystin 1 and polycystin 2 are needed for kidney function; loss of polycystin function leads to autosomal dominant polycystic kidney disease (ADPKD). Polycystins localize to cilia in C. elegans and mammals, a finding that has guided research into ADPKD. The discovery that the polycystins form ciliary receptors in male-specific neurons needed for mating behaviors has also helped to unlock insights into two additional exciting new areas: the secretion of extracellular vesicles; and mechanisms of ciliary specialization. First, we will summarize the studies done in C. elegans regarding the expression, localization, and function of the polycystin 1 and 2 homologs, LOV-1 and PKD-2, and discuss insights gained from this basic research. Molecules that are co-expressed with the polycystins in the male-specific neurons may identify evolutionarily conserved molecular mechanisms for polycystin function and localization. We will discuss the finding that polycystins are secreted in extracellular vesicles that evoke behavioral change in males, suggesting that such vesicles provide a novel form of communication to conspecifics in the environment. In humans, polycystin-containing extracellular vesicles are secreted in urine and can be taken up by cilia, and quickly internalized. Therefore, communication by polycystin-containing extracellular vesicles may also use mechanisms that are evolutionarily conserved from nematode to human. Lastly, different cilia display structural and functional differences that specialize them for particular tasks, despite the fact that virtually all cilia are built by a conserved Intraflagellar Transport (IFT) mechanism and share some basic structural features. Comparative analysis of the male-specific cilia with the well-studied cilia of the amphid and phasmid neurons has allowed identification of molecules that specialize the male cilia. We will discuss the molecules that shape the male-specific cilia. The cell biology of cilia in male-specific neurons demonstrates that C. elegans can provide an excellent model of ciliary specialization.

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Non-Motile Primary Cilia as Fluid Shear Stress Mechanosensors

Cited by 56 publications

References 53 publications

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways

Pulsed electromagnetic fields promote osteoblast mineralization and maturation needing the existence of primary cilia

Mating behavior, male sensory cilia, and polycystins in Caenorhabditis elegans

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