Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein

Bansal, Megha; Moharir, Shivranjani C; Sailasree, S Purnima; Sirohi, Kapil; Sudhakar, Cherukuri; Sarathi, D. Partha; Lakshmi, B. Jyothi; Buono, Mario; Kumar, Satish; Swarup, Ghanshyam

doi:10.1074/jbc.m117.801944

Cited by 78 publications

(72 citation statements)

References 60 publications

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“…Previous studies showed that p62 plays an important role in the degradation of poly-ubiquitinated proteins under the condition of UPS impairment (Demishtein et al, 2017;Kageyama et al, 2014;Milan et al, 2015;Pankiv et al, 2007). In this study, we demonstrated that p-p62 S403 (Bansal et al, 2018;Chang & Monteiro, 2015;Sundaramoorthy et al, 2017). Taken together, all the evidence suggests that UPS dysfunction may be one of core pathogenic mechanisms of ALS.…”

Section: Discussionsupporting

confidence: 55%

PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

Lee

Jeon

Kim

et al. 2018

Preprint

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Therefore, targeting PTK2-TBK1-p62 axis may represent a novel therapeutic intervention for neurodegenerative diseases with TDP-43 proteinopathy.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Discussionsupporting

confidence: 55%

PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

Lee

Jeon

Kim

et al. 2018

Preprint

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“…Similar channeling of Rab8a to ATG8CL-autophagosomes occurs during carbon starvation (Figure 4), suggesting that PexRD54 could mimic a host autophagy adaptor that regulates autophagy under nutrient deprivation. Interestingly, the mammalian autophagy cargo receptor Optineurin also interacts with both LC3 (mammalian ATG8 isoform) and Rab8a in mice (Bansal et al, 2018; Vaibhava et al, 2012). Although the functional implications of these interactions are unclear, a proposed model suggests that Optineurin mediates pre-autophagosomal membrane elongation through anchoring Rab8a to autophagosome assembly sites.…”

Section: Discussionmentioning

confidence: 99%

The Irish potato famine pathogen subverts host vesicle trafficking to channel starvation-induced autophagy to the pathogen interface

Pandey

Leary

Tümtaş

et al. 2020

Preprint

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Eukaryotic cells deploy autophagy to eliminate invading microbes. In turn, pathogens have evolved 22 effector proteins to counteract antimicrobial autophagy. How and why adapted pathogens co-opt 23 autophagy for their own benefit is poorly understood. The Irish famine pathogen Phythophthora 24 infestans secretes the effector protein PexRD54 that selectively activates an unknown plant 25 autophagy pathway, while antagonizing antimicrobial autophagy. Here we show that PexRD54 26 induces autophagosome formation by bridging small GTPase Rab8a-decorated vesicles with 27 autophagic compartments labelled by the core autophagy protein ATG8CL. Rab8a is required for 28 pathogen-triggered and starvation-induced but not antimicrobial autophagy, revealing that specific 29 trafficking pathways underpin selective autophagy. We discovered that Rab8a contributes to basal 30 immunity against P. infestans, but PexRD54 diverts a sub-population of Rab8a vesicles to lipid 31 droplets that associate with autophagosomes. These are then diverted towards pathogen feeding 32 structures that are accommodated within the host cells. We propose that PexRD54 mimics starvation-33 induced autophagy by channeling host endomembrane trafficking towards the pathogen interface 34 possibly to acquire nutrients. This work reveals that effectors can interconnect independent host 35 compartments to stimulate complex cellular processes that benefit the pathogen. Graphical abstract: 37 38 39 40 41 42 43 44 45 Introduction: 46 47Autophagy is a conserved eukaryotic cellular process that mediates the lysosomal degradation and 48 relocation of cellular cargoes within double-membraned vesicles called autophagosomes (He and 49 Klionsky, 2009; Leidal et al., 2020). Although autophagy is historically considered to be a bulk 50 catabolic pathway tasked with maintaining cellular homeostasis under normal or stress conditions, it 51 is now clear that autophagy can be highly selective in cargo choice (Zaffagnini and Martens, 2016). 52Autophagic cargoes are typically captured during autophagosome formation, a complex process that 53 is regulated by the concerted action of a set of conserved autophagy related proteins (ATG) as well 54 as specialized autophagy adaptors and cargo receptors (Mizushima et al., 2011). These captured 55 cargoes are sorted within the autophagosome during maturation of the isolation membrane (also 56 known as the phagophore) via the specific interactions between cargo receptors and a lipidated form 57 of ATG8, which decorates the phagophore to serve as a docking platform for cargo receptors 58 (Ryabovol and Minibayeva, 2016; Slobodkin and Elazar, 2013). 60The source of the phagophore is still under debate, but its primary source is considered to be the 61 endoplasmic reticulum (ER) (Bernard and Klionsky, 2013; Hamasaki et al., 2013). As the cargo is 62 being captured, the phagophore undergoes massive expansion and finally gets sealed to form a 63 mature autophagosome. Therefore, formation of the autophagosome requires additional lipid supplies 64...

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“…Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3: Optineurin mediates autophagy dependent clearance of protein aggregates formed by mHtt and some other mutant proteins associated with neurodegenerative diseases in neuronal and non-neuronal cells (29,30). Recently we have generated Optn -/mouse embryonic fibroblasts (MEFs) which show reduced non-selective (basal and starvation induced) autophagy as seen by reduced formation of LC3-II, and lower number of autophagosomes and autolysosomes in comparison with wild type cells (36,44). We examined the formation of mHtt aggregates in Optn -/and wild type MEFs by expressing GFP tagged mHtt and observing under a fluorescence microscope.…”

Section: Resultsmentioning

confidence: 99%

Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates

Moharir¹,

Ak²,

Swarup³

2020

Preprint

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Optineurin (OPTN), a cytoplasmic adaptor protein involved in cargo selective autophagy of bacteria, damaged mitochondria and mutant protein aggregates, is frequently seen in pathological structures containing protein aggregates, associated with several neurodegenerative diseases. However, the function of OPTN in these protein aggregates is not known. Here, we have explored the role of OPTN in mutant protein aggregation and in cytoprotection from toxicity of mutant proteins. Mutant huntingtin (mHtt) and mutant ataxin-3 (mAtax-3) showed reduced formation of aggregates in Optn-/- mouse embryonic fibroblasts as compared with wild type cells. Co-expression of OPTN enhanced aggregate formation by mHtt and mAtax-3 in Optn-/- cells. C-terminal domain of OPTN (412-577 amino acids) was necessary and sufficient to promote aggregate formation by these mutant proteins. The E478G mutant of OPTN, defective in ubiquitin-binding and autophagy, was also able to promote aggregation of mHtt and mAtax-3. OPTN and its C-terminal domain form a complex with the chaperone HSP70 known to promote mutant protein aggregation. Overexpression of mHtt or mAtax-3 induced more cell death in Optn-/- cells compared with wild type cells. Importantly, compared to wild type cells, Optn-deficient cells having mHtt or mAtax-3 aggregates showed higher level of cell death in neuronal (N2A) and non-neuronal cells. Our results show that OPTN promotes formation of mutant huntingtin and mutant ataxin-3 aggregates, and this function of OPTN might be mediated through interaction with HSP70 chaperones. Our results also show that OPTN reduces cytotoxicity caused by these mutant protein aggregates.

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Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein

Cited by 78 publications

References 60 publications

PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

The Irish potato famine pathogen subverts host vesicle trafficking to channel starvation-induced autophagy to the pathogen interface

Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates

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