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A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

ABSTRACT: Primary cilia function as critical signaling hubs whose absence leads to severe disorders collectively known as ciliopathies; our knowledge of ciliogenesis remains limited. We show that Smo induces ciliogenesis through two distinct yet essential noncanonical Hh pathways in several cell types, including neurons. Surprisingly, ligand activation of Smo induces autophagy via an LKB1-AMPK axis to remove the satellite pool of OFD1. This is required, but not sufficient, for ciliogenesis. Additionally, Smo activates the Gαi-LGN-NuMA-dynein axis, causing accumulation of a portion of OFD1 at centrioles in early ciliogenesis. Both pathways are critical for redistribution of BBS4 from satellites to centrioles, which is also mediated by OFD1 centriolar translocation. Notably, different Smo agonists, which activate Smo distinctly, activate one or the other of these pathways; only in combination they recapitulate the activity of Hh ligand. These studies provide new insight into physiological stimuli (Hh) that activate autophagy and promote ciliogenesis and introduce a novel role for the Gαi-LGN-NuMA-dynein complex in this process.

SUBMITTER: Akhshi T

PROVIDER: S-EPMC7714386 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

Akhshi Tara T Trimble William S WS

The Journal of cell biology 20210101 1

Primary cilia function as critical signaling hubs whose absence leads to severe disorders collectively known as ciliopathies; our knowledge of ciliogenesis remains limited. We show that Smo induces ciliogenesis through two distinct yet essential noncanonical Hh pathways in several cell types, including neurons. Surprisingly, ligand activation of Smo induces autophagy via an LKB1-AMPK axis to remove the satellite pool of OFD1. This is required, but not sufficient, for ciliogenesis. Additionally, ...[more]

PMID: 33258871

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Project description:BackgroundGlioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.MethodsU251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.ResultsHere we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth.ConclusionOur findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion.

Dataset Information

A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

Publications

A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

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