The assembly and function of the primary cilium depends on multimolecular intraflagellar transport (IFT) complexes that shuttle their cargo along the axonemal microtubules through their interaction with molecular motors. The IFT system has been moreover recently implicated in a reciprocal interplay between autophagy and ciliogenesis. We have previously reported that IFT20 and other components of the IFT complexes participate in the assembly of the immune synapse in the non-ciliated T cell, suggesting that other cellular processes regulated by the IFT system in ciliated cells, including autophagy, may be shared by cells lacking a cilium. Starting from the observation of a defect in autophagic clearance and an accumulation of lipid droplets in IFT20-deficient T cells, we show that IFT20 is required for lysosome biogenesis and function by controlling the lysosomal targeting of acid hydrolases. This function involves its ability to regulate the retrograde traffic of the cation-independent mannose-6-phosphate receptor (CI-MPR) to the trans-Golgi network, which is achieved by coupling recycling CI-MPRs to the microtubule motor dynein. Consistent with the lysosomal defect, an upregulation of the TFEB-dependent expression of the lysosomal gene network can be observed in IFT20-deficient cells, which is associated with defective tonic T-cell antigen receptor signaling and mTOR activity. We additionally show that the lysosome-related function of IFT20 extends to non-ciliated cells other than T cells, as well as to ciliated cells. Our findings provide the first evidence that a component of the IFT system that controls ciliogenesis is implicated in the biogenesis of lysosomes.
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The authors wish to thank Greg Pazour for critically reading the paper and for generously providing anti-IFT20 antibodies and constructs, Roman Polishchuk for critically reading the paper and for his help on the electron microscopy analysis. They also wish to thank Francesco Cecconi, Claire Hivroz, Laurence Bataille, Roberto Zoncu, Diego Medina, Alberto Luini, Francesco Nardi, and Marco Telford for useful discussions and suggestions. The GFP-TFEB construct was generously provided by Diego Medina and the hTERT cells by Paola Marcolongo. This work was carried out with the generous support of Telethon - Italy (Grant GGP16003). The CTB lab is also supported by a grant from AIRC (Grant IG 20148). VC is supported by the Lundbeck Foundation (R209–2015–3505) and the KBVU from the Danish Cancer Society (R146-A9471).
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Finetti, F., Cassioli, C., Cianfanelli, V. et al. The intraflagellar transport protein IFT20 controls lysosome biogenesis by regulating the post-Golgi transport of acid hydrolases. Cell Death Differ 27, 310–328 (2020). https://doi.org/10.1038/s41418-019-0357-y
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