Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway

Kageyama, Shun; Sou, Yu‐shin; Uemura, Takefumi; Kametaka, Satoshi; Saito, Tetsuya; Ishimura, Ryosuke; Kouno, Tsuguka; Bedford, Lynn; Mayer, R. John; Lee, Myung-Shik; Yamamoto, Masayuki; Waguri, Satoshi; Tanaka, Keiji; Komatsu, Masaaki

doi:10.1074/jbc.m114.580357

Cited by 101 publications

(90 citation statements)

References 41 publications

(34 reference statements)

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“…To explain the synergistic control of Dronc protein levels by the UPS and autophagy, we considered that, because the UPS and autophagy are mechanistically linked, impairment of the UPS can enhance autophagy, which is often referred to as compensatory autophagy 1,[19][20][21][22][23][24][25][26][27] (reviewed by Park and Cuervo, 3 Wojcik 28 and Lamark and Johansen 29 ). For example, in Drosophila, compensatory autophagy after proteasome impairment has been reported in neurons, in fat body cells and in adult flies.…”

Section: Simultaneous Inactivation Of Both the Proteasome And Autophamentioning

confidence: 99%

“…16 The incorporation of Atg8 fusion proteins (for example, with green fluorescent protein (GFP) and/or mCherry) into autophagosomes is often used as a marker for autophagosomes 17 and autophagic flux. 18 Although it was initially assumed that the UPS and autophagy are independent of each other, recent evidence has suggested that there is crosstalk and feedback between the two 1,[19][20][21][22][23][24][25][26][27] (reviewed by Park and Cuervo, 3 Wojcik 28 and Lamark and Johansen 29 ). This is mostly due to the observation that autophagy can also degrade ubiquitylated proteins.…”

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confidence: 99%

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The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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Section: Simultaneous Inactivation Of Both the Proteasome And Autophamentioning

confidence: 99%

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confidence: 99%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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“…The ubiquitin-proteasome system and autophagy are crucial for maintaining the proteostasis and are interdependent pathways. In mice with reduced proteasome activity in their livers, proteasome dysfunction activated autophagy and KEAP1/NRF2 pathway [58]. Recently, NRF2 has been identified as a regulator of autophagy gene expression [59] indicating its potential in regulating cellular proteostasis (Figure 1).…”

Section: Nrf2 Modulation Of Proteostasis Oxidative Stress and Inflammentioning

confidence: 99%

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

Lastres‐Becker¹

2017

J Alzheimers Dis Parkinsonism

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“…During this process, as BHMT are normally highly enriched on the membranes of autophagosomes or their precursors, 51,52 they are passively packaged into autophagosomes and subsequently processed. In the absence of the cargo receptors, aggresomes cannot form, 52,53 thereby abolishing the MAP1LC3-mediated autophagosome formation and the parallel sequestration of BHMT. Many other possibilities exist and many questions remain, including whether and how the multimeric BHMT are preferentially associated with autophagosome membranes, that need to be further addressed in the future.…”

Section: Different Mechanisms Mediate Starvation-and Proteasome Inhibmentioning

confidence: 99%

“…Further, cargo receptors SQSTM1 and NBR1 not only recognize and bind to ubiquitinated proteins, but are also required for their assembly into aggregate-like structures (aggresomes) that are important for their subsequent recognition and sequestration by the MAP1LC3-containing autophagosome structures, as supported by the findings that loss of SQSTM1 significantly suppresses the accumulation of ubiquitinated proteins as well as the formation of inclusion bodies both in autophagy-deficient neurons and hepatocytes, and also in hepatocytes with impaired proteasome activity that otherwise show elevated levels of ubiquitinated aggregates. 53,54 Given these observations, one putative scenario is that upon proteasomal impairment, cargo receptors SQSTM1 and NBR1 recruit ubiquitinated proteins into aggresomes, a prerequisite step for their recognition by the MAP1LC3-containing membranes that subsequently assemble into mature autophagosomes. During this process, as BHMT are normally highly enriched on the membranes of autophagosomes or their precursors, 51,52 they are passively packaged into autophagosomes and subsequently processed.…”

Section: Different Mechanisms Mediate Starvation-and Proteasome Inhibmentioning

confidence: 99%

The GST-BHMT assay reveals a distinct mechanism underlying proteasome inhibition-induced macroautophagy in mammalian cells

Rui

Chen

et al. 2015

Autophagy

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#These authors equally contributed to this work.Keywords: BHMT, cargo receptors SQSTM1/p62 and NBR1, MTOR, PRKAA/AMPK, proteasome inhibition, selective macroautophagyAbbreviations: ACACA/B, acetyl-CoA carboxylase a/b; ACTB, actin, b; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATG7, autophagy-related 7; Baf A1, bafilomycin A 1 ; BCL2, B-cell CLL/lymphoma 2; BECN1, Beclin 1, autophagy-related; BHMT, betaine-homocysteine S-methyltransferase; CTNNB1, catenin (cadherin-associated protein), b 1, 88kDa; Cvt, cytoplasm-to-vacuole-targeting; DDIT3, DNA-damage-inducible transcript 3; EBSS, Earle's Balanced Salt Solution; EIF2AK3, eukaryotic translation initiation factor 2-a, kinase 3; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; ERN1, endoplasmic reticulum to nucleus signaling 1; GST, glutathionine S-transferase; GST-BHMT, a fusion protein of glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase; GST-BHMT (FRAG) , an autophagy-mediated cleavage product of the GST-BHMT reporter; HA, hemagglutinin; HSPA5, heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa); LSCS, linker-specific cleavage site; MAP1LC3, microtubule-associated protein 1 light chain 3; MAP2K7, mitogen-activated protein kinase kinase 7; MAPK8, mitogen-activated protein kinase 8; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, MTOR complex 1; NBR1, neighbor of BRCA1 gene 1; P4HB, prolyl 4-hydroxylase, b polypeptide; PRKAA, protein kinase, AMP-activated, a catalytic subunit; RHEB, Ras homolog enriched in brain; RM, rich medium; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TSC1/2, tuberous sclerosis 1/2; ULK1, unc-51 like autophagy activating kinase 1; UPR, unfolded protein response; UPS, ubiquitin proteasome system; XBP1, X-box binding protein 1By monitoring the fragmentation of a GST-BHMT (a protein fusion of glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase) reporter in lysosomes, the GST-BHMT assay has previously been established as an endpoint, cargo-based assay for starvation-induced autophagy that is largely nonselective. Here, we demonstrate that under nutrient-rich conditions, proteasome inhibition by either pharmaceutical or genetic manipulations induces similar autophagy-dependent GST-BHMT processing. However, mechanistically this proteasome inhibition-induced autophagy is different from that induced by starvation as it does not rely on regulation by MTOR (mechanistic target of rapamycin [serine/threonine kinase]) and PRKAA/AMPK (protein kinase, AMP-activated, a catalytic subunit), the upstream central sensors of cellular nutrition and energy status, but requires the presence of the cargo receptors SQSTM1/p62 (sequestosome 1) and NBR1 (neighbor of BRCA1 gene 1) that are normally involved in the selective autophagy pathway. Further, it depends on ER (endoplasmic reticulum) stress signaling, in particular ERN1/IRE1 (endoplasmic ...

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Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway

Cited by 101 publications

References 41 publications

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

The GST-BHMT assay reveals a distinct mechanism underlying proteasome inhibition-induced macroautophagy in mammalian cells

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