Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux

Kim, Hyo Jeong; Kim, Sunyong; Kim, Daeho; Park, Joon Seong; Jeong, Seong Hyun; Choi, Young Won; Kim, Chul‐Ho

doi:10.1080/15548627.2020.1740529

Cited by 35 publications

(38 citation statements)

References 57 publications

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“…Given that mitochondria are a major source of ROS and a central regulator of apoptosis, the role of ATE1 in this organelle may provide an explanation for its observed involvement in the stress response (Bongiovanni et al, 1999;Decca et al, 2007;Carpio et al, 2010Carpio et al, , 2013Lopez Sambrooks et al, 2012;Deka et al, 2016;Kumar et al, 2016;Birnbaum et al, 2019;Kim et al, 2020). Future studies will be devoted to understanding whether the translocation of ATE1 into mitochondria (or other cellular compartments such as the nucleus) is influenced by stress.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

Jiang

Moorthy

Patel

et al. 2020

Front. Cell Dev. Biol.

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Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

Jiang

Moorthy

Patel

et al. 2020

Front. Cell Dev. Biol.

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“…Anticancer agents Rhus coriaria, SC66 and Vitamin C can stimulate ubiquitination and degradation of AKT in cancer cells [95,96]. When proteasome impairs in cellular stress, E3 ligase MUL1 catalyzes K48-linked ubiquitination of AKT, which subsequently undergoes lysosomal degradation, playing key roles in cellular survival [97]. This process can be reversed by DUB USP7 [97].…”

Section: Ubiquitination Of Aktmentioning

confidence: 99%

“…When proteasome impairs in cellular stress, E3 ligase MUL1 catalyzes K48-linked ubiquitination of AKT, which subsequently undergoes lysosomal degradation, playing key roles in cellular survival [97]. This process can be reversed by DUB USP7 [97].…”

Section: Ubiquitination Of Aktmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

281

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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“…Of these, the ubiquitin chain formed at the K48 position mainly mediates proteasomal degradation, while the K63 ubiquitin chain affects protein activity and localization (Bhoj and Chen, 2009 ; Yang et al, 2010 ). AKT K48 chains formed by E3 ligases such as MUL1 (Kim et al, 2020 ), TTC3 (Suizu et al, 2009 ) and RNF8 (Zhu et al, 2020 ) were found to mediate AKT protein degradation and inactivation, whereas ubiquitination of AKT K63 residues mediated by TRAF6 (Yang et al, 2009 ) or SKP2-SCF (Chan et al, 2012 ) E3 ligases plays a key regulatory role in the membrane localization and phosphorylation activation of AKT. Interestingly, the AKT1(E17K) mutant exhibits stronger levels of ubiquitination than AKT1(WT), and blocking this ubiquitination process significantly reduces Akt membrane recruitment and phosphorylation, while overexpression of TRAF6 can further increase AKT1(E17K) ubiquitination levels (Yang et al, 2009 ; Li et al, 2013 ).…”

Section: Possible Molecular Mechanisms By Which the E17k Mutation Impmentioning

confidence: 99%

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

Chen

Huang

Dong

et al. 2020

Front. Cell Dev. Biol.

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The substitution of the seventeenth amino acid glutamate by lysine in the homologous structural domain of the Akt1 gene pleckstrin is a somatic cellular mutation found in breast, colorectal, and ovarian cancers, named p. Glu17Lys or E17K. In recent years, a growing number of studies have suggested that this mutation may play a unique role in the development of tumors. In this review article, we describe how AKT1(E17K) mutations stimulate downstream signals that cause cells to emerge transformed; we explore the differential regulation and function of E17K in different physiological and pathological settings; and we also describe the phenomenon that E17K impedes tumor growth by interfering with growth-promoting and chemotherapy-resistant AKT1 low QCC generation, an intriguing finding that mutants may prolong tumor patient survival by activating feedback mechanisms and disrupting transcription. This review is intended to provide a better understanding of the role of AKT1(E17K) in cancer and to inform the development of AKT1(E17K)-based antitumor strategies.

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Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux

Cited by 35 publications

References 57 publications

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

The role of ubiquitination and deubiquitination in cancer metabolism

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

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