Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling

Mao, Suifang; Shah, Alok S.; Moninger, Thomas O.; Ostedgaard, Lynda S.; Lu, Lijun; Tang, Xiao Xiao; Thornell, Ian M.; Reznikov, Leah R.; Ernst, Sarah E.; Karp, Philip H.; Tan, Ping; Keshavjee, Shaf; Alaiwa, Mahmoud H. Abou; Welsh, Michael J.

doi:10.1073/pnas.1719177115

Cited by 32 publications

(42 citation statements)

References 53 publications

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“…The dogma whereby motile cilia simply clear the airways has now been expanded by studies demonstrating that they also possess mechanosensory traits. It is now understood that respiratory cilia share chemosensory abilities once thought unique to primary cilia, long known to be involved in chemosensation, signal transduction, and regulation of cellular growth (51,87,122,146,170). Studies have also shown possible involvement of cilia in lung repair processes (148,155) and in regulating cytokine and antimicrobial production (11,56,131), thus suggesting an even greater involvement of these organelles in lung function than initially thought.…”

Section: Respiratory Cilia: Structure Function and Expressionmentioning

confidence: 99%

“…Recently, the delineation between motile cilia and primary cilia functions have blurred. Key signaling proteins such as hedgehog and smoothened, once thought unique to primary cilia, are also expressed in motile cilia (122). Moreover, in the airway epithelium, the expression of primary cilia is required for subsequent development of motile cilia (88).…”

Section: Chemosensory Functions Of Airway Ciliamentioning

confidence: 99%

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First contact: the role of respiratory cilia in host-pathogen interactions in the airways

Kuek

Lee

2020

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Respiratory cilia are the driving force of the mucociliary escalator, working in conjunction with secreted airway mucus to clear inhaled debris and pathogens from the conducting airways. Respiratory cilia are also one of the first contact points between host and inhaled pathogens. Impaired ciliary function is a common pathological feature in patients with chronic airway diseases, increasing susceptibility to respiratory infections. Common respiratory pathogens including viruses, bacteria and fungi have been shown to target cilia and/or ciliated airway epithelial cells, resulting in a disruption of mucociliary clearance that may facilitate host infection. Despite being an integral component of airway innate immunity, the role of respiratory cilia and their clinical significance during airway infections is still poorly understood. This review examines the expression, structure, and function of respiratory cilia during pathogenic infection of the airways. This review also discusses specific known points of interaction of bacteria, fungi, and viruses with respiratory cilia function. The emerging biological functions of motile cilia relating to intracellular signaling and their potential immuno-regulatory roles during infection will also be discussed.

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Section: Respiratory Cilia: Structure Function and Expressionmentioning

confidence: 99%

Section: Chemosensory Functions Of Airway Ciliamentioning

confidence: 99%

First contact: the role of respiratory cilia in host-pathogen interactions in the airways

Kuek

Lee

2020

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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“…We next asked how AC6 affects Kif19a protein levels. Given the recently established role of autophagy in ciliogenesis (10,11) and the interconnected AMPK-autophagy pathways, we proceeded to test whether the components of autophagy and AMPK pathway are altered in Adcy6 D/D epithelial cells. Indeed, up-regulated AMPK signaling, for example, increased P-AMPK-a-Thr 172 and down-regulation of P-mTOR were observed in Adcy6 D/D isolated MTECs relative to the control (Fig.…”

Section: Kif19a Is An Autophagy Substratementioning

confidence: 99%

“…Primary cilium length is known to be sensitive to intracellular cAMP dependent upon AC5/6 activity (9). In the context of motile cilia, the role of cAMP is known to be as an important regulator of ciliary beating and organization of compartmental signaling (10,11). Whether ACs and cAMP regulate motile cilia growth and development has not been explored before.…”

mentioning

confidence: 99%

AC6 regulates the microtubule-depolymerizing kinesin KIF19A to control ciliary length in mammals

Arora

Lund

Naren

et al. 2020

Journal of Biological Chemistry

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Motile cilia are hair like structures that line respiratory and reproductive tract, and middle ear, and generate fluid flow in these organs via synchronized beating. Cilium growth is a highly regulated process that is assumed to be important for flow generation. Recently, Kif19a, a kinesin residing at the cilia tip, was identified to be essential for ciliary length control through its microtubule depolymerization function. However, there is lack of information on the nature of proteins and the integrated signaling mechanism regulating growth of motile cilia. Here, we report that adenylate cyclase 6 (AC6), a highly abundant AC isoform in airway epithelial cells, inhibits degradation of Kif19a by inhibiting autophagy, a cellular recycling mechanism for damaged proteins and organelles. Using epithelium specific knockout mice of AC6, we demonstrated that AC6 knockout (KO) airway epithelial cells have longer cilia compared to the wild-type cells due to decreased Kif19a protein levels in the cilia. We demonstrated in vitro that AC6 inhibits AMP-activated kinase (AMPK), an important modulator of cellular energy conserving mechanisms, and uncouples its binding with ciliary kinesin Kif19a. In the absence of AC6, activation of AMPK mobilizes Kif19a into autophagosomes for degradation in airway epithelial cells. Lower Kif19a levels upon pharmacological activation of AMPK in airway epithelial cells correlated with elongated cilia and vice versa. In all, AC6-AMPK pathway, that is tunable to cellular cues could potentially serve as one of the crucial ciliary growth checkpoints, and could be channeled to develop therapeutic interventions for cilia-associated disorders.

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“…Equally interestingly, not only secreted Shh ligand can be found right outside of the apical side (motile ciliated side) of the airway, Shh pathway components (Ptch, Smo, SUFU, Gli) were also found in motile cilia. Furthermore, Shh signaling in motile cilia was most likely via the non-canonical fashion involving cyclic adenosine monophosphate (cAMP) [ 55 ].…”

Section: Canonical and Non-canonical Shh Pathway Activationmentioning

confidence: 99%

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Leprieur

Costantini

Ding

et al. 2018

IJMS

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Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

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Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling

Cited by 32 publications

References 53 publications

First contact: the role of respiratory cilia in host-pathogen interactions in the airways

First contact: the role of respiratory cilia in host-pathogen interactions in the airways

AC6 regulates the microtubule-depolymerizing kinesin KIF19A to control ciliary length in mammals

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

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