Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62′s Role in Neurodegenerative Disease

Wooten, Marie W.; Hu, Xiaoyun; Babu, Jeganathan Ramesh; Seibenhener, M. Lamar; Geetha, Thangiah; Paine, Michael G.; Wooten, Michael C.

doi:10.1155/jbb/2006/62079

Cited by 97 publications

(104 citation statements)

References 86 publications

(132 reference statements)

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“…α‐Internexin, a neural intermediate filament protein implicated in both AD (Dickson et al ., 2005) and ALS (Page et al ., 2011), was consistently enriched in AD tau‐IP aggregates (Table 2). Sequestosome‐1, which helps to recruit misfolded proteins and their aggregates to either proteasomes or autophagosomes (Wooten et al ., 2006), was highly enriched in tau‐IP aggregates exclusively when derived from AD (Tables 1 and 2). In that context, it is not surprising that tau/Aβ 1–4 PLA signal also colocalizes with punctate immunostain for LC3B/ATG8, a marker of autophagosome membranes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…Misfolded proteins may result from mutation or as a consequence of conditions, such as oxidative stress, that favor protein unfolding. 13,14,15,18,20 Oxidative stress is also a classical inducer of p62 6,19,24 and therefore seems to be the central player in these disease processes. Moreover, keratin mutations prime hepatocytes to oxidative injury and may thus predispose patients to liver cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

“…19 However, in a certain context inclusion bodies also may be cytotoxic. 4,[12][13][14][15][16][17][18][19][20][21][22][23][24] The aim of our studies was to obtain closer insight into MB and IHB formation by in vitro transfection of their major components, keratins, p62, and ubiquitin, and correlating the ultrastructure of the resulting aggregates with their chemical composition. Keratin 8 was primarily chosen because we and others have shown that keratin 8 is essential for MB formation in vivo.…”

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confidence: 99%

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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“…In response to selinexor alone, Western blot analysis revealed prompt processing and accumulation of LC3 II (Fig. 1A) and sequestosome 1 (p62), an LC3-interacting protein and scavenger of ubiquitinated proteins fated for degradation via autophagy that is also consumed by autophagy (19). Caspase-10 levels decreased modestly during the course of treatment, which is associated with the induction of autophagy in myeloma cells (12).…”

Section: Sine and Pi Treatment Both Induce Hallmarks Of Apoptosis Andmentioning

confidence: 96%

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

Rosebeck

Alonge

Kandarpa

et al. 2016

Molecular Cancer Therapeutics

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Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60-71. Ó2015 AACR.

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Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62′s Role in Neurodegenerative Disease

Cited by 97 publications

References 86 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

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

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

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