Essential Role of Sequestosome 1/p62 in Regulating Accumulation of Lys63-ubiquitinated Proteins

Wooten, Marie W.; Geetha, Thangiah; Babu, Jeganathan Ramesh; Seibenhener, M. Lamar; Peng, Junmin; Cox, Nancy R.; Diaz-Meco, Marı́a T.; Moscat, Jorge

doi:10.1074/jbc.m709496200

Cited by 160 publications

(166 citation statements)

References 30 publications

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“…Recently, it has been reported that ubiquitination targets substrates for protein degradation via both pathways [33,34], which underscores the importance of the crosstalk between the UPS and autophagy for cell viability [35][36][37][38]. Autophagy is functionally coupled to the activity of the UPS to protect from cell death by repression of UPS in tumor cells [35].…”

Section: Discussionmentioning

confidence: 99%

“…Two hESC lines (CHA15-hESC [23], passages 55-85, and H9, passages 50-80) and a human induced pluripotent stem cell (iPSC) line [24] (passages [25][26][27][28][29][30][31][32][33][34][35] were used in this study. They were maintained on Mitomycin C (Sigma-Aldrich, St. Louis, MO, http://www.sigmaaldrich.com)-treated mouse embryonic fibroblasts (mct-MEFs) in the ESC medium at 37 C and 5% CO 2 in air.…”

Section: Chemical Treatments In Hescsmentioning

confidence: 99%

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Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cho¹,

Han²,

Kim³

et al. 2014

Stem Cells

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The pluripotency of embryonic stem cells (ESCs) is maintained by intracellular networks of many pluripotency-associated (PA) proteins such as OCT4, SOX2, and NANOG. However, the mechanisms underlying the regulation of protein homeostasis for pluripotency remain elusive.Here, we first demonstrate that autophagy acts together with the ubiquitin-proteasome system (UPS) to modulate the levels of PA proteins in human ESCs (hESCs). Autophagy inhibition impaired the pluripotency despite increment of PA proteins in hESCs. Immunogold-electron microscopy confirmed localization of OCT4 molecules within autophagosomes. Also, knockdown of LC3 expression led to accumulation of PA proteins and reduction of pluripotency in hESCs. Interestingly, autophagy and the UPS showed differential kinetics in the degradation of PA proteins. Autophagy inhibition caused enhanced accumulation of both cytoplasmic and nuclear PA proteins, whereas the UPS inhibition led to preferentially degrade nuclear PA proteins. Our findings suggest that autophagy modulates homeostasis of PA proteins, providing a new insight in the regulation of pluripotency in hESCs. STEM CELLS 2014;32:424-435

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Section: Discussionmentioning

confidence: 99%

Section: Chemical Treatments In Hescsmentioning

confidence: 99%

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cho¹,

Han²,

Kim³

et al. 2014

Stem Cells

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“…65 How and why restrictionsensitive virus alters the degradative fate of TRIM5a remains unclear. However, as p62 mediates both proteasomal 64,66 and autophagic degradation, [67][68][69] it may play a role in dictating the degradative fate of TRIM5a.…”

Section: Sastri and Campbell Cellular Degradation Of Trim5amentioning

confidence: 99%

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

Sastri

Campbell

2011

AIDS Research and Human Retroviruses

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The cellular factor TRIM5a inhibits infection by numerous retroviruses in a species-specific manner. The TRIM5a protein from rhesus macaques (rhTRIM5a) restricts infection by HIV-1 while human TRIM5a (huTRIM5a) restricts infection by murine leukemia virus (MLV). In owl monkeys a related protein TRIM-Cyp restricts HIV-1 infection. Several models have been proposed for retroviral restriction by TRIM5 proteins (TRIM5a and TRIMCyp). These models collectively suggest that TRIM5 proteins mediate restriction by directly binding to specific determinants in the viral capsid. Through their ability to self-associate TRIM5 proteins compartmentalize the viral capsid core and mediate its abortive disassembly via a poorly understood mechanism that is sensitive to proteasome inhibitors. In this review, we discuss TRIM5-mediated restriction in detail. We also discuss how polymorphisms within human and rhesus macaque populations have been demonstrated to affect disease progression of immunodeficiency viruses in these species.

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“…5B and Fig. S5B) (34,35). Because loss of KIF2A was suggested to induce autophagy, as a consequence of decreased mTORC1 activity (15), we tested whether loss of KIF2C also promotes autophagy.…”

Section: Cancer-cell Transformation Unlinks the Nutrient Sensitivity mentioning

confidence: 99%

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Zaganjor¹,

Weil²,

Gonzales³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The kinesin family members (KIFs) KIF2A and KIF2C depolymerize microtubules, unlike the majority of other kinesins, which transport cargo along microtubules. KIF2A regulates the localization of lysosomes in the cytoplasm, which assists in activation of the mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. We find that the closely related kinesin KIF2C also influences lysosomal organization in immortalized human bronchial epithelial cells (HBECs). Expression of KIF2C and, to a lesser extent, KIF2A in untransformed and mutant K-Ras-transformed cells is regulated by ERK1/2. Prolonged inhibition of ERK1/2 activation with PD0325901 mimics nutrient deprivation by disrupting lysosome organization and decreasing mTORC1 activity in HBEC, suggesting a long-term mechanism for optimization of mTORC1 activity by ERK1/2. We tested the hypothesis that up-regulation of KIF2C and KIF2A by ERK1/2 caused aberrant lysosomal positioning and mTORC1 activity in a mutant K-Ras-dependent cancer and cancer model. In Ras-transformed cells, however, mTORC1 activity and lysosome organization appear independent of ERK1/2 and these kinesins although ERK1/2 activity and the kinesins are required for Ras-dependent proliferation and migration. We conclude that mutant K-Ras repurposes these signaling and regulatory proteins to support the transformed phenotype.

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Essential Role of Sequestosome 1/p62 in Regulating Accumulation of Lys63-ubiquitinated Proteins

Cited by 160 publications

References 30 publications

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

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