Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression

Liu, Zhengzhao; Chen, Peng; Gao, Hong; Gu, Yu; Jiao, Yang; Peng, Hong; Xu, Xingxing; Wang, Haifeng; Yang, Meiqiang; Li, Xiaoying; Фан, Ли; Chen, Shiyao; Zhou, Jian; Sun, Yihong; Ruan, Kangchen; Cheng, Shuqun; Komatsu, Masaaki; White, Eileen; Li, Lin; Ji, Hongbin; Finley, Daniel; Hu, Ronggui

doi:10.1016/j.ccr.2014.05.015

Cited by 202 publications

(222 citation statements)

References 49 publications

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“…Yet another mind-boggling prospect is that p62 ubiquitylation creates high-complexity scaffolds that await their characterization. Thus, another Ub-binding adapter, Optineurin, when ubiquitylated, recruits p62 as previously shown by the same group [9]. A very tight interplay between Ub-binding receptors, i.e., p62, NBR1, Optineurin, NDP52, TAX1BP1, and Tollip/Cue5 can now be expected ( Figure 1B).…”

supporting

confidence: 75%

Love laughs at Locksmiths: Ubiquitylation of p62 unlocks its autophagy receptor potential

Conway

Kirkin

2017

Cell Res

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supporting

confidence: 75%

Love laughs at Locksmiths: Ubiquitylation of p62 unlocks its autophagy receptor potential

Conway

Kirkin

2017

Cell Res

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“…Autophagy has been linked to tumor suppression in liver, breast, lung, and kidney cancers (19,(27)(28)(29)(30)(31). Similarly, we showed that prostate tumor growth is enhanced when autophagy is negatively regulated.…”

Section: Discussionmentioning

confidence: 56%

Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy

Puto

Brognard

Hunter

2015

Journal of Biological Chemistry

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Background: Transcriptional repressor DAXX suppresses several tumor suppressor genes and is up-regulated in many cancers. Results: We demonstrate that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Conclusion: In the early stages of tumorigenesis, autophagy suppresses prostate tumor formation. Significance: This is the first study to link prostate cancer development to autophagy suppression by DAXX.

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“…Consistently, selective autophagy via p62 is enhanced via the autophagy agonist metformin in a dose-dependent manner, whereas silencing of autophagy with the modulator BECLIN1 attenuates the process (24). A recent study showed that HACE1 proteins play an intricate role in mediating autophagy flux by promoting optineurin-ubiquitin-p62 conjugation (38). Physical linkages between autophagy adaptor proteins via polyubiquitin chains are required for autophagy flux.…”

Section: Discussionmentioning

confidence: 89%

Metformin increases degradation of phospholamban via autophagy in cardiomyocytes

Teng

Miyake

Yokoe

et al. 2015

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

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Phospholamban (PLN) is an effective inhibitor of the sarco(endo) plasmic reticulum Ca 2+ ATPase (SERCA). Here, we examined PLN stability and degradation in primary cultured mouse neonatal cardiomyocytes (CMNCs) and mouse hearts using immunoblotting, molecular imaging, and [ 35 S]methionine pulse-chase experiments, together with lysosome (chloroquine and bafilomycin A1) and autophagic (3-methyladenine and Atg5 siRNA) antagonists. Inhibiting lysosomal and autophagic activities promoted endogenous PLN accumulation, whereas accelerating autophagy with metformin enhanced PLN degradation in CMNCs. This reduction in PLN levels was functionally correlated with an increased rate of SERCA2a activity, accounting for an inotropic effect of metformin. Metabolic labeling reaffirmed that metformin promoted wild-type and R9C PLN degradation. Immunofluorescence showed that PLN and the autophagy marker, microtubule light chain 3, became increasingly colocalized in response to chloroquine and bafilomycin treatments. Mechanistically, pentameric PLN was polyubiquitinylated at the K3 residue and this modification was required for p62-mediated selective autophagy trafficking. Consistently, attenuated autophagic flux in HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1-null mouse hearts was associated with increased PLN levels determined by immunoblots and immunofluorescence. Our study identifies a biological mechanism that traffics PLN to the lysosomes for degradation in mouse hearts.selective autophagy | ubiquitinylation | protein degradation P hospholamban (PLN) is a 52-amino acid peptide located in the sarcoplasmic reticulum (SR) membrane in cardiac, slowtwitch skeletal, and smooth muscle, where it exists as a monomer or pentamer. Whereas monomeric PLN physically interacts with sarco(endo)plasmic reticulum Ca 2+ ATPase type 2a (SERCA2a) to antagonize its function, pentameric PLN complexes are thought to be a reservoir of inactive PLN (1-3). The physical interaction between SERCA2a and PLN reduces the apparent affinity of SERCA2a for Ca 2+ , thereby making SERCA2a less active in transporting Ca 2+ from the cytoplasm to the lumen of the SR at the same concentration of cytoplasmic Ca 2+. The physical interaction between the two proteins is regulated by phosphorylation of PLN at Ser16 by protein kinase A or at Thr17 by Ca 2+ /calmodulin-dependent protein kinase II (2). Phosphorylation of PLN reduces its affinity for SERCA2a, thereby increasing SERCA2a activity (2). Evidence from transgenic mice also supports the inhibitory function of PLN. Although targeted PLN deletion enhances baseline cardiac performance, cardiac-specific overexpression of superinhibitory forms of PLN leads to decreases in the affinity of SERCA2a for Ca 2+ (2). These observations underscore the primary role of PLN as a regulator of SERCA2a activity and, therefore, as a crucial regulator of cardiac contractility. PLN inhibition of SERCA2a can be reversed by either external (i.e., activation of β-adrenergic receptors) or internal (i.e., increased...

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Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression

Cited by 202 publications

References 49 publications

Love laughs at Locksmiths: Ubiquitylation of p62 unlocks its autophagy receptor potential

Love laughs at Locksmiths: Ubiquitylation of p62 unlocks its autophagy receptor potential

Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy

Metformin increases degradation of phospholamban via autophagy in cardiomyocytes

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