Keeping proteasomes under control—a role for phosphorylation in the nucleus

Sha, Zhe; Peth, Andreas; Goldberg, Alfred L.

doi:10.1073/pnas.1115315108

Cited by 21 publications

(16 citation statements)

References 24 publications

(21 reference statements)

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“…The degradation of ubiquitin conjugates by the 26S proteasome is coupled to ATP hydrolysis 36 , and ATP enhances multiple steps in this process, including conjugate binding, deubiquitination, substrate unfolding, gate opening in the 20S particle 22,37 and substrate trans-location into the 20S central chamber 21 . Protein aggregates, such as tau, that bind the 26S particle but resist dissociation or translocation through the ATPases, could disrupt this multistep process and obstruct the degradation of other proteins.…”

Section: Discussionmentioning

confidence: 99%

Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Myeku

Clelland

Emrani

et al. 2015

Nat Med

370

320

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The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP–protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.

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Section: Discussionmentioning

confidence: 99%

Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Myeku

Clelland

Emrani

et al. 2015

Nat Med

370

320

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“…Thus, one means by which melatonin could influence proteasome activity is through phosphorylation of the RPT6 subunit. Sha et al [102] have pointed out that regulating phosphorylation of proteasome subunits is one way of controlling the activity of proteasomes. Protein kinase A has also been reported to phosphorylate RPT6 [103].…”

Section: Melatonin and The Proteasomementioning

confidence: 99%

Melatonin feedback on clock genes: a theory involving the proteasome

Vriend

Reíter

2014

Journal of Pineal Research

211

159

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The expression of 'clock' genes occurs in all tissues, but especially in the suprachiasmatic nuclei (SCN) of the hypothalamus, groups of neurons in the brain that regulate circadian rhythms. Melatonin is secreted by the pineal gland in a circadian manner as influenced by the SCN. There is also considerable evidence that melatonin, in turn, acts on the SCN directly influencing the circadian 'clock' mechanisms. The most direct route by which melatonin could reach the SCN would be via the cerebrospinal fluid of the third ventricle. Melatonin could also reach the pars tuberalis (PT) of the pituitary, another melatonin-sensitive tissue, via this route. The major 'clock' genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. Clock and Bmal1 heterodimers act on E-box components of the promoters of the Per and Cry genes to stimulate transcription. A negative feedback loop between the cryptochrome proteins and the nucleus allows the Cry and Per proteins to regulate their own transcription. A cycle of ubiquitination and deubiquitination controls the levels of CRY protein degraded by the proteasome and, hence, the amount of protein available for feedback. Thus, it provides a post-translational component to the circadian clock mechanism. BMAL1 also stimulates transcription of REV-ERBa and, in turn, is also partially regulated by negative feedback by REV-ERBa. In the 'black widow' model of transcription, proteasomes destroy transcription factors that are needed only for a particular period of time. In the model proposed herein, the interaction of melatonin and the proteasome is required to adjust the SCN clock to changes in the environmental photoperiod. In particular, we predict that melatonin inhibition of the proteasome interferes with negative feedback loops (CRY/PER and REV-ERBa) on Bmal1 transcription genes in both the SCN and PT. Melatonin inhibition of the proteasome would also tend to stabilize BMAL1 protein itself in the SCN, particularly at night when melatonin is naturally elevated. Melatonin inhibition of the proteasome could account for the effects of melatonin on circadian rhythms associated with molecular timing genes. The interaction of melatonin with the proteasome in the hypothalamus also provides a model for explaining the dramatic 'time of day' effect of melatonin injections on reproductive status of seasonal breeders. Finally, the model predicts that a proteasome inhibitor such as bortezomib would modify circadian rhythms in a manner similar to melatonin.

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“…The two inner rings contain the β-subunits. Within the β-rings, β1, β5 and β2 are the catalytic subunits and cleave after acidic, hydrophobic, and basic amino acid residues, respectively [8,9]. The standard proteasome is highly abundant in skeletal muscle and is responsible for degrading ubiquitinated proteins.…”

Section: Introductionmentioning

confidence: 99%

Denervation-Induced Activation of the Standard Proteasome and Immunoproteasome

et al. 2016

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The standard 26S proteasome is responsible for the majority of myofibrillar protein degradation leading to muscle atrophy. The immunoproteasome is an inducible form of the proteasome. While its function has been linked to conditions of atrophy, its contribution to muscle proteolysis remains unclear. Therefore, the purpose of this study was to determine if the immunoproteasome plays a role in skeletal muscle atrophy induced by denervation. Adult male C57BL/6 wild type (WT) and immunoproteasome knockout lmp7-/-/mecl-1-/- (L7M1) mice underwent tibial nerve transection on the left hindlimb for either 7 or 14 days, while control mice did not undergo surgery. Proteasome activity (caspase-, chymotrypsin-, and trypsin- like), protein content of standard proteasome (β1, β5 and β2) and immunoproteasome (LMP2, LMP7 and MECL-1) catalytic subunits were determined in the gastrocnemius muscle. Denervation induced significant atrophy and was accompanied by increased activities and protein content of the catalytic subunits in both WT and L7M1 mice. Although denervation resulted in a similar degree of muscle atrophy between strains, the mice lacking two immunoproteasome subunits showed a differential response in the extent and duration of proteasome features, including activities and content of the β1, β5 and LMP2 catalytic subunits. The results indicate that immunoproteasome deficiency alters the proteasome’s composition and activities. However, the immunoproteasome does not appear to be essential for muscle atrophy induced by denervation.

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Keeping proteasomes under control—a role for phosphorylation in the nucleus

Cited by 21 publications

References 24 publications

Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Melatonin feedback on clock genes: a theory involving the proteasome

Denervation-Induced Activation of the Standard Proteasome and Immunoproteasome

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