Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation

Sha, Zhe; Schnell, Helena M.; Ruoff, Kerstin; Goldberg, Alfred L.

doi:10.1083/jcb.201708168

Cited by 81 publications

(92 citation statements)

References 74 publications

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“…Following substrate ubiquitylation, p62 (or other adaptors) binds to poly-ubiquitinated proteins via the UBA domain. Increasing evidence revealed the crosstalk and reciprocal regulatory mechanisms between the two pathways, by which useless materials that accumulate following inhibition of one degradative system could be cleared by the other system [18][19][20]. We previously revealed starvation induced nuclear export of deacetylated LC3, which became the resource of membrane-associated LC3 [3,17].…”

Section: Discussionmentioning

confidence: 99%

“…Despite of the different mechanisms, ubiquitylation is the degradation signal by both systems. Increasing evidence revealed the crosstalk and reciprocal regulatory mechanisms between the two pathways, by which useless materials that accumulate following inhibition of one degradative system could be cleared by the other system [18][19][20]. The proteasome-mediated degradation of LC3 is one mechanism of autophagy regulation by proteasome.…”

Section: Discussionmentioning

confidence: 99%

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Acetylation modulates LC3 stability and cargo recognition

Song

Yin

et al. 2019

FEBS Letters

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LC3 is a key autophagy‐related protein involved in both autophagosome formation and autophagy cargo recruitment. Despite these functions being exerted by deacetylated LC3, this protein is more abundantly distributed in its acetylated form. Here, we reveal that the stability and cargo recognition ability of LC3 are highly dependent on its acetylation. Through detecting the diffusion rate of soluble LC3 by fluorescence recovery after photobleaching (FRAP), we found that nutrient‐state‐related acetylation inhibited LC3 complex formation. Acetylation blocked LC3's interaction with p62, the autophagic cargo receptor, preventing the mis‐targeting of p62 to nonautophagic LC3 and thus permitting the efficient degradation of autophagic cargoes. Acetylation also inhibited LC3 proteasome‐dependent degradation, thus maintaining LC3 as a long‐lived protein that could serve as a reserve. Altogether, acetylated LC3, the nonactivated form, is suitable for storage and avoids inopportune interactions with other proteins, assuring autophagic degradation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acetylation modulates LC3 stability and cargo recognition

Song

Yin

et al. 2019

FEBS Letters

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“…A study using fruit flies showed that HDAC6 mediated autophagic activation by proteasome inhibition; 41 however, PSMI does not appear to upregulate HDAC6 in mammalian cells. 45 Several transcription factors such as p53, 46,47 Nrf2, 48 and NFκB, 49,50 have been shown to regulate the transcription of a subset of autophagy genes.…”

Section: Proteasome Malfunction Activates Tfebmentioning

confidence: 99%

The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction

Pan

Parajuli

Tian

et al. 2019

Preprint

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ABSTRACTRationaleThe ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime for example, show cardiotoxicity. Moreover, UPS and ALP defects are implicated in the pathogenesis of a large subset of heart disease. Hence, a better understanding of the cross-talk between the two catabolic pathways should help advance cardiac pathophysiology and medicine.ObjectiveSystemic pharmacological proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. The present study investigates whether cardiomyocyte-restricted PSMI activates myocardial ALP and, more importantly, how proteasome malfunction activates the ALP in the heart.Methods and ResultsMyocardial macroautophagy, transcription factor EB (TFEB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (a 19S proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted markedly by calcineurin inhibition (cyclosporine A) and by siRNA-mediated Molcn1 silence. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null mice. In cultured wild type, but not p62-null, mouse cardiomyocytes, PSMI induced increases in LC3-II flux and in the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62 null mice compared with wild type mice.Conclusions(1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) both Mocln1 and p62 form a feed-forward loop with TFEB during TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac ALP activation in a proteasome malfunction setting.

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“…Babu et al, 2005). However, it was suggested that the condensates function to sequester ubiquitylated proteins in neuroblastoma cells (Sha et al, 2018). How substrate sequestration and autophagosome formation are coordinated is an important open question (Fig.…”

Section: P62-ubiquitin Condensates As Substrates For Autophagymentioning

confidence: 99%

p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy

Danieli

Martens

2018

Journal of Cell Science

120

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The degradation of misfolded proteins is essential for cellular homeostasis. Misfolded proteins are normally degraded by the ubiquitin-proteasome system (UPS), and selective autophagy serves as a backup mechanism when the UPS is overloaded. Selective autophagy mediates the degradation of harmful material by its sequestration within double-membrane organelles called autophagosomes. The selectivity of autophagic processes is mediated by cargo receptors, which link the cargo to the autophagosomal membrane. The p62 cargo receptor (SQSTM1) has a main function during the degradation of misfolded, ubiquitylated proteins by selective autophagy; here it functions to phase separate these proteins into larger condensates and tether them to the autophagosomal membrane. Recent work has given us crucial insights into the mechanism of action of the p62 cargo receptor during selective autophagy and how its activity can be integrated with the UPS. We will discuss these recent insights in the context of protein quality control and the emerging concept of cellular organization mediated by phase transitions.

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Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation

Cited by 81 publications

References 74 publications

Acetylation modulates LC3 stability and cargo recognition

Acetylation modulates LC3 stability and cargo recognition

The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction

p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy

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