FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates

Abstract

The protein kinase TBK1 is a central regulator of innate immune responses and autophagy, and ablation of either function has been linked to neuroinflammatory or degenerative diseases. Autophagy is an intracellular process that recycles old or damaged proteins and organelles. In recent years, the TBK1-dependent regulation of autophagy pathways has been characterized. However, the autophagy-dependent regulation of TBK1 activity awaits further clarification. Here, we observed that TBK1 is recruited to SQSTM1/p62-containing aggregates via the selective autophagy receptor TAX1BP1. In these aggregates, TBK1 phosphorylates SQSTM1/p62 at serine 403 and thus presumably regulates the efficient engulfment and clearance of these structures. We found that TBK1 activation is strongly increased if FIP200, a component of the autophagy-inducing ULK1 complex, is not present or cannot bind to TAX1BP1. Given our collective findings, we hypothesize that FIP200 ensures the inducible activation of TBK1 at SQSTM1/p62 condensates.

TBK1 is part of a galectin 8 dependent membrane damage recognition complex and drives autophagy upon Adenovirus endosomal escape

“…Tank binding kinase (TBK1) has recently been implicated in autophagy activation. It is recruited by autophagy receptors to damaged organelles such as mitochondria [ 24 ], aggregates [ 25 ], or lysosomes [ 26 ], leading to their elimination. TBK1 is also involved in the degradation of invasive bacteria by autophagy, following detection of cellular membrane penetration by galectins.…”

“…Gal8 is also responsible for local activation of TBK1 [ 27 ]. Activated TBK1 promotes the phosphorylation of autophagy receptors including NDP52 [ 27 ], p62 [ 25 ], optineurin [ 28 ] and Tax1BP1 [ 29 ]. Phosphorylation of the receptors is thought to drive sustained autophagy activation [ 28 , 29 ].…”

Non-canonical function of FIP200 is required for neural stem cell maintenance and differentiation by limiting TBK1 activation and p62 aggregate formation

“…Although several studies including the current manuscript demonstrated TBK1 activation upon FIP200 deletion in different cells 46 , the mechanisms involved are not well understood at present. Our previous studies suggested that FIP200 interaction with a TBK1 adaptor molecule, AZI2, may serve to restrict TBK1 activation in other cells 28 .…”

Digest it all: the lysosomal turnover of cytoplasmic aggregates

“…This series of events is also sustained by the observation that p62, NBR1, and TAX1BP1 are associated with protein aggregates even in the absence of an intact ATG machinery [57]. In addition, TAX1BP1 recruits the TBK1 kinase to protein aggregates, leading to the phosphorylation of p62, a post-translational modification that enhances p62 binding to Ub [58]. This function appears to be regulated by FIP200 [58], indicating that the recruitment of SARs to aggregates not only guides their recognition by the ATG machinery but also serves for their own feedback regulation to enhance cargo binding and clustering.…”

“…In addition, TAX1BP1 recruits the TBK1 kinase to protein aggregates, leading to the phosphorylation of p62, a post-translational modification that enhances p62 binding to Ub [58]. This function appears to be regulated by FIP200 [58], indicating that the recruitment of SARs to aggregates not only guides their recognition by the ATG machinery but also serves for their own feedback regulation to enhance cargo binding and clustering. In line with the current view of the mechanism of selective types of autophagy (Box 3), p62 bodies are also a platform for autophagosome generation [45].…”