TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

Guerroué, François Le; Werner, Achim; Wang, Chunxin; Youle, Richard J.

doi:10.1101/2022.03.14.484269

Cited by 3 publications

(2 citation statements)

References 44 publications

(76 reference statements)

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“…In contrast to our data, this group reported LIR1 of murine TNIP1 as being responsive to TLR1/TLR2 activation by LPS ( Shinkawa et al, 2022 ). In another very recent study, TNIP1 was shown to negatively interfere with mitophagy by interfering with ULK1 complex dynamics ( Le Guerroue et al, 2022 Preprint ). In accordance with our results, these authors reported that LIR2 mutation abolished all binding to ATG8 proteins, while LIR1 mutations had no effect on binding.…”

Section: Discussionmentioning

confidence: 99%

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

Zhou

Rasmussen

Olsvik

et al. 2022

Journal of Cell Biology

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Limitation of excessive inflammation due to selective degradation of pro-inflammatory proteins is one of the cytoprotective functions attributed to autophagy. In the current study, we highlight that selective autophagy also plays a vital role in promoting the establishment of a robust inflammatory response. Under inflammatory conditions, here TLR3-activation by poly(I:C) treatment, the inflammation repressor TNIP1 (TNFAIP3 interacting protein 1) is phosphorylated by Tank-binding kinase 1 (TBK1) activating an LIR motif that leads to the selective autophagy-dependent degradation of TNIP1, supporting the expression of pro-inflammatory genes and proteins. This selective autophagy efficiently reduces TNIP1 protein levels early (0–4 h) upon poly(I:C) treatment to allow efficient initiation of the inflammatory response. At 6 h, TNIP1 levels are restored due to increased transcription avoiding sustained inflammation. Thus, similarly as in cancer, autophagy may play a dual role in controlling inflammation depending on the exact state and timing of the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

Zhou

Rasmussen

Olsvik

et al. 2022

Journal of Cell Biology

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“…For example, the induction of xenophagy upon bacterial invasion in mammalian cells requires the association of the protein kinase TBK1 with FIP200, which is mediated by two adaptor proteins, NAP1/SINTBAD, containing FIP200 binding motifs 37 . TNIP1 negatively regulates mammalian mitophagy in parts by binding to FIP200 via a potential FIP200 interaction motif 47 . FIP200 also binds Atg16L1 via a FIP200 interaction motif to promote starvation-induced autophagy in mammalian cells 48,49 .…”

Section: Discussionmentioning

confidence: 99%

A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy

Gross

Ghillebert

Schuetter

et al. 2022

Preprint

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Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here, we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, we find core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 during pexophagy when TORC1 remains active under phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits not only bind selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.

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A20 binding and inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1): a novel modulator of mitochondrial autophagy

Merline

Rödig

Zeng-Brouwers

et al. 2023

American Journal of Physiology-Cell Physiology

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A20 binding inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1), a polyubiquitin-binding protein, is a signal-induced autophagy receptor that attenuates NF-κB-mediated inflammation and cell death. The present study aimed to elucidate the potential role of ABIN-1 in mitophagy, a biological process whose outcome is decisive in diverse physiological and pathological settings. Microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II) was found to be in complex with ectopically expressed hemagglutinin (HA)-tagged-full length (FL)-ABIN-1. Bacterial expression of ABIN-1 and LC3A and LC3B showed direct binding of ABIN-1 to LC3 proteins, while mutations in the LC3-interacting region (LIR) 1 and 2 motifs of ABIN-1 abrogated ABIN-1/LC3B-II complex formation. Importantly, induction of autophagy in HeLa cells resulted in co-localization of ABIN-1 with LC3B-II in autophagosomes and with lysosomal associated membrane protein 1 (LAMP-1) in autophagolysosomes, leading to co-degradation of ABIN-1 with p62. Interestingly, ABIN-1 was found to translocate to damaged mitochondria in HeLa-mCherry-Parkin cells. In line with this observation, CRISPR/Cas9-mediated deletion of ABIN-1 significantly inhibited the degradation of the mitochondrial outer membrane proteins voltage-dependent anion-selective channel 1 (VDAC-1), mitofusin-2 (MFN2), and translocase of outer mitochondrial membrane (TOM)20. Additionally, siRNA-mediated knockdown of ABIN-1 significantly decreased lysosomal uptake of mitochondria in HeLa cells expressing mCherry-Parkin and the fluorescence reporter mt-mKEIMA. Collectively, our results identify ABIN-1 as a novel and selective mitochondrial autophagy regulator that promotes mitophagy, thereby adding a new player to the complex cellular machinery regulating mitochondrial homeostasis.

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TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

Cited by 3 publications

References 44 publications

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy

A20 binding and inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1): a novel modulator of mitochondrial autophagy

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