The Intraflagellar Transport Protein IFT20 Recruits ATG16L1 to Early Endosomes to Promote Autophagosome Formation in T Cells

Abstract

Lymphocyte homeostasis, activation and differentiation crucially rely on basal autophagy. The fine-tuning of this process depends on autophagy-related (ATG) proteins and their interaction with the trafficking machinery that orchestrates the membrane rearrangements leading to autophagosome biogenesis. The underlying mechanisms are as yet not fully understood. The intraflagellar transport (IFT) system, known for its role in cargo transport along the axonemal microtubules of the primary cilium, has emerged as a regulator of autophagy in ciliated cells. Growing evidence indicates that ciliogenesis proteins participate in cilia-independent processes, including autophagy, in the non-ciliated T cell. Here we investigate the mechanism by which IFT20, an integral component of the IFT system, regulates basal T cell autophagy. We show that IFT20 interacts with the core autophagy protein ATG16L1 and that its CC domain is essential for its pro-autophagic activity. We demonstrate that IFT20 is required for the association of ATG16L1 with the Golgi complex and early endosomes, both of which have been identified as membrane sources for phagophore elongation. This involves the ability of IFT20 to interact with proteins that are resident at these subcellular localizations, namely the golgin GMAP210 at the Golgi apparatus and Rab5 at early endosomes. GMAP210 depletion, while leading to a dispersion of ATG16L1 from the Golgi, did not affect basal autophagy. Conversely, IFT20 was found to recruit ATG16L1 to early endosomes tagged for autophagosome formation by the BECLIN 1/VPS34/Rab5 complex, which resulted in the local accumulation of LC3. Hence IFT20 participates in autophagosome biogenesis under basal conditions by regulating the localization of ATG16L1 at early endosomes to promote autophagosome biogenesis. These data identify IFT20 as a new regulator of an early step of basal autophagy in T cells.

Multiple ciliary localization signals control INPP5E ciliary targeting

“…Recent work shows that INPP5E ciliary targeting requires ATG16L1, an autophagy protein that forms a complex with IFT-B complex component IFT20 ( Boukhalfa et al, 2021 ; Finetti et al, 2021 ). Moreover, ATG16L1 was shown to interact with INPP5E and its product PI4P ( Boukhalfa et al, 2021 ).…”

Autophagy and the primary cilium in cell metabolism: What’s upstream?

“…In addition, the ciliary proteins IFT20, OFD1 (Finetti et al, 2021;Morleo et al, 2021) and ATG16L1 (Boukhalfa et al, 2021) are engaged in the regulation of autophagy and ciliogenesis, respectively.…”

“…As such, the word “ciliophagy” has been adequately introduced to designate the selective degradation of ciliary proteins by the autophagic pathway ( Cloonan et al, 2014 ). In addition, the ciliary proteins IFT20, OFD1 ( Finetti et al, 2021 ; Morleo et al, 2021 ) and ATG16L1 ( Boukhalfa et al, 2021 ) are engaged in the regulation of autophagy and ciliogenesis, respectively.…”

Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting

“…Recent work shows that INPP5E ciliary targeting requires ATG16L1, an autophagy protein that forms a complex with IFT-B complex component IFT20 68,88 . Moreover, ATG16L1 was shown to interact with INPP5E, and with its product PI4P 68 .…”