26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation

VerPlank, Jordan J. S.; Lokireddy, Sudarsanareddy; Zhao, Jinghui; Goldberg, Alfred L.

doi:10.1073/pnas.1809254116

Cited by 101 publications

(129 citation statements)

References 38 publications

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“…The p38 MAPK inhibitor PD169316 was identified as the most potent activator of the proteasome by chemical genetic screening [155]. Furthermore, hormones-like epinephrine were shown to phosphorylate Rpn6 (the 19S regulatory subunit of the 26S proteasome complex) to thereby activate proteasome function in the heart and thereby increase cardiac output [156]. Thus, pharmacological strategies to activate proteasomal function appear to be beneficial in animals but translation to humans has yet to be investigated.…”

Section: Pharmacological and Nutraceutical Interventionsmentioning

confidence: 99%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

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Section: Pharmacological and Nutraceutical Interventionsmentioning

confidence: 99%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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“…The activity of the proteasome is regulated by different regulators in a number of various physiological pathways. For example, activated PKA by raising cAMP can phosphorylate proteasome subunit Rpn6, leading to an increase to the hydrolysis activity of the proteasome 15 . Additionally, RAD6 promotes the activity of the proteasome by enhancing the degradation of PSMF1 16 .…”

Section: Introductionmentioning

confidence: 99%

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Zhang

et al. 2020

Cell Death Dis

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T cell homeostasis is critical for the proper function of the immune system. Following the sharp expansion upon pathogen infection, most T cells die in order to keep balance in the immune system, a process which is controlled by death receptors during the early phase and Bcl-2 proteins in the later phase. It is still highly debated whether the apoptosis of T cells is determined from the beginning, upon activation, or determined later during the contraction. MCL1, a Bcl-2 family member, plays a pivotal role in T cell survival. As a fast turnover protein, MCL1 levels are tightly regulated by the 26S proteasome-controlled protein degradation process. In searching for regulatory factors involved in the actions of MCL1 during T cell apoptosis, we found that ALG-2 was critical for MCL1 stability, a process mediated by a direct interaction between ALG-2 and Rpn3, a key component of the 26S proteasome. As a critical calcium sensor, ALG-2 regulated the activity of the 26S proteasome upon increases to cytosolic calcium levels following T cell activation, this consequently influenced the stability of MCL1 and accelerated the T cell "death" process, leading to T cell contraction and restoration of immune homeostasis. Our study provides support for the notion that T cells are destined for apoptosis after activation, and echoes the previous study about the function of ALG-2 in T cell death.

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“…Similarly, phosphorylation of the constitutive 19S subunit Rpn6 by protein kinase A promoted assembly of 26S complexes upon mTOR inhibition [55,56]. Such activation of 26S proteasome function under conditions of mTOR inhibition parallels that of autophagy induction to ensure cellular amino acids supply [40].…”

Section: Discussionmentioning

confidence: 99%

Adaptive mitochondrial regulation of the proteasome

Meul

2020

Preprint

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The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Regulation of proteasome function by mitochondrial metabolism, however, is unknown.Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome in the absence of oxidative stress. Impaired respiratory complex I function leads to metabolic reprogramming of the Krebs cycle and deficiency in aspartate. Aspartate supplementation activates assembly and activity of 26S proteasomes via transcriptional activation of the proteasome assembly factors p28 and Rpn6. This metabolic adaptation of 26S proteasome function involves sensing of aspartate via the mTORC1 pathway. Metformin treatment of primary human cells similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, respiratory dysfunction conferred resistance towards the proteasome inhibitor Bortezomib.Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications. 4 Keywords 26S proteasome, mitochondria, respiratory complex I, aspartate, metabolic reprogramming, proteasome assembly factors, pyruvate 5

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26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation

Cited by 101 publications

References 38 publications

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Adaptive mitochondrial regulation of the proteasome

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