p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

Zatloukal, Kurt; Stumptner, Cornelia; Fuchsbichler, Andrea; Heid, Hans; Schnoelzer, Martina; Kenner, Lukas; Kleinert, R.; Prinz, Marco; Aguzzi, Adriano; Denk, Helmut

doi:10.1016/s0002-9440(10)64369-6

Cited by 572 publications

(465 citation statements)

References 46 publications

(36 reference statements)

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“…1,46,47 In fact, in several settings, p62/SQSTM1 alleviates, the cytotoxic effects of aggregated proteins by inducing their degradation. [42][43][44][45][46] We established, here, that p62/SQSTM1 operates as a cell survival signal for AML cells that undergo granulocyte differentiation. Furthermore, we showed that p62/SQSTM1 mitigates the effects of accumulation of aggregated proteins during ATRA-induced differentiation of APL cells.…”

Section: Discussionmentioning

confidence: 80%

“…Because p62/SQSTM1 is known to interact with ubiquitinated proteins, [42][43][44][45] we next examined whether the increase in p62/SQSTM1 protein levels by ATRA treatment of APL NB4 cells was associated with an accumulation of polyubiquitinated proteins. We used western blotting to assess the distribution of polyubiquitinated proteins into the Triton X-100-insoluble protein fractions prepared from NB4 extracts.…”

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p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

et al. 2014

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The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-jB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34 þ progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a prosurvival function of the NF-jB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.

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Section: Discussionmentioning

confidence: 80%

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p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

et al. 2014

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“…57 In addition, an important adaptor protein for autophagy, p62/ SQSTM1, can be detected in aggregates in the ATZ liver (see below). 58 In cells overexpressing ATZ, autophagosomes seem to be closely juxtaposed with the ATZ aggregates, and suppressing autophagy retards the removal of ATZ. 59 Furthermore, in the yeast model of ATZ degradation, it has also been found that aggregated ATZ is targeted to the autophagy pathway for degradation.…”

Section: Role Of Autophagy In Clearing Misfolded Proteins In Liver DImentioning

confidence: 99%

“…55 One particularly interesting common feature of these inclusion bodies is that they are all stained positive for p62/ SQSTM1. 58,76 p62/SQSTM1 could serve as an important adaptor molecule, binding both the ubiquitin moiety of the misfolded proteins and LC3/Atg8 on the autophagosome. 77,78 LC3 and p62 have been found to colocalize with mutant huntingtin, which seem to be codegraded in autophagolysosomes.…”

Section: Role Of Autophagy In Clearing Misfolded Proteins In Liver DImentioning

confidence: 99%

Autophagy in the liver

2008

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A great part of our current understanding of mammalian macroautophagy is derived from studies of the liver. The term "autophagy" was introduced by Christian de Duve in part based on ultrastructural changes in rat liver following glucagon injection. Subsequent morphological, biochemical, and kinetics studies of autophagy in the liver defined the basic process of autophagosome formation, maturation, and degradation and the regulation of autophagy by hormones, phosphoinositide 3-kinases, and mammalian target of rapamycin. It is now clear that macroautophagy in the liver is important for the balance of energy and nutrients for basic cell functions, the removal of misfolded proteins resulting from genetic mutations or pathophysiological stimulations, and the turnover of major subcellular organelles such as mitochondria, endoplasmic reticulum, and peroxisomes under both normal and pathophysiological conditions. Disturbance of autophagy function in the liver could thus have a major impact on liver physiology and liver disease. (HEPATOLOGY 2008;47: 1773-1785.)

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“…Moreover, p62 contains a binding site for the tumor necrosis factor receptor-associated factor 6, which is an E3 ubiquitin ligase, two PEST (regions rich in proline, glutamate, serine, and threonine) sequences, and the ubiquitin-association (UBA) domain. [5][6][7] We have recently described the simultaneous occurrence of MBs and IHBs in neoplastic (hepatocellular carcinoma) and non-neoplastic (idiopathic copper toxicosis) hepatocytes, and of "hybrid" inclusions consisting of both Abbreviations: cDNA, complementary deoxyribonucleic acid; DDC,3, Ig, immunoglobulin; IHB, intracellular hyaline body; MB, Mallory body; p62, sequestosome 1/p62; UBA, …”

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In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

et al. 2007

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M allory bodies (MBs) and intracellular hyaline bodies (IHBs) are hepatocellular inclusions that may occur in a diversity of chronic liver disorders. 1,2 They differ in their light and electron microscopic appearance and chemical composition but share sequestosome 1/p62 (p62) as a major component. [1][2][3][4] Whereas MBs contain in addition abnormal keratins, ubiquitin, and heat shock proteins, keratins are lacking in classical IHBs. 1,4 P62 is a multifunctional protein 5,6 with several structural motifs that determine its various functions: the SH2 domain binds the tyrosine kinase p56 lck in a phosphotyrosine-independent manner, an acidic interaction domain associates with the atypical protein kinase C and mediates the role of p62 as adapter in tumor necrosis factor alpha-initiated, interleukin-1-initiated, and nerve growth factor-initiated signal transduction, and a ZZ-type zinc finger binds the receptor interactive protein involved in tumor necrosis factor-induced apoptosis. Moreover, p62 contains a binding site for the tumor necrosis factor receptor-associated factor 6, which is an E3 ubiquitin ligase, two PEST (regions rich in proline, glutamate, serine, and threonine) sequences, and the ubiquitin-association (UBA) domain. [5][6][7] We have recently described the simultaneous occurrence of MBs and IHBs in neoplastic (hepatocellular carcinoma) and non-neoplastic (idiopathic copper toxicosis) hepatocytes, and of "hybrid" inclusions consisting of both Abbreviations: cDNA, complementary deoxyribonucleic acid; DDC,3, Ig, immunoglobulin; IHB, intracellular hyaline body; MB, Mallory body; p62, sequestosome 1/p62; UBA,

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p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

Cited by 572 publications

References 46 publications

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

Autophagy in the liver

In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

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