Proteasome Function Is Regulated by Cyclic AMP-dependent Protein Kinase through Phosphorylation of Rpt6

Zhang, Fengxue; Hu, Yong; Huang, Ping; Toleman, Clifford A.; Paterson, Andrew J.; Kudlow, Jeffrey E.

doi:10.1074/jbc.m702439200

Cited by 186 publications

(199 citation statements)

References 43 publications

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“…For example, decreased expression of Rpn11, a 19 S RP subunit, was found to be associated with aging (59), a condition known be accompanied by increased ROS formation (60). Additional indirect effects of H 2 O 2 on proteasomal activity may be due to modulation of redox-sensitive signaling pathways, including those involving protein kinase A (61,62), that participate in the phosphorylation of Rpt6, an AAA ATPase subunit, which contributes to 26 S proteasomal function (63).…”

Section: Discussionmentioning

confidence: 99%

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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Although increased intracellular concentrations of hydrogen peroxide (H 2 O 2 ) are associated with inhibition of 26 S proteasomal activity, the mechanisms responsible for such effects have not been well delineated. In the present studies, we found that direct exposure of purified 26 S proteasomes to H 2 O 2 had negligible effects on their activity, whereas incubation with glutathione and H 2 O 2 produced >80% decrease in chymotrypsin-like and trypsin-like activities. Rpn1 and Rpn2, which are subunits of the 19 S regulatory particle, undergo S-glutathionylation after exposure of purified 26 S proteasomes to glutathione and H 2 O 2 , as well as in HEK 293 cells and neutrophils incubated with H 2 O 2 . Increased oxidation of Rpn1 and Rpn2 cysteine thiols was also found in lung extracts from mice in which catalase was inactivated, a condition associated with augmented intracellular concentrations of H 2 O 2 and diminished 26 S proteasomal activity. Although unoxidized Rpn2 enhanced 20 S proteolytic function in vitro, such potentiation was not found when the 20 S core particle was incubated with oxidized Rpn2. The composition of 26 S proteasomes was not altered after exposure to glutathione and H 2 O 2 , with similar amounts of Rpn1 and Rpn2 in control or oxidized 26 S proteasomal complexes. These findings identify S-glutathionylation of Rpn2 as a contributory mechanism for H 2 O 2 -induced inhibition of 26 S proteasomal function.The ubiquitin-proteasomal system is a major pathway for protein degradation and is involved in multiple cellular processes, including cell cycle control, expression of cell surface receptors, and regulation of intracellular levels of structural and regulatory proteins and transcription factors (1-6). The 26 S proteasome is composed of two main components, a proteolytic 20 S core particle (CP) 2 and an ATPase containing 19 S regulatory particle (RP) (7-10). Ubiquitinated proteins are unfolded in the 19 S RP and then translocated into the 20 S CP where they are degraded. The 20 S CP is composed of four heptameric rings of ␣ and ␤ subunits, with the two inner ␤ rings having proteolytic activity. The 19 S RP consists of a lid and base subcomplex, with the base subcomplex, including the nonenzymatic Rpn1 and Rpn2 toroids, surrounded by six AAA-type ATPases. Rpn1 and Rpn2 appear to play a major regulatory role by modulating the translocation and subsequent degradation of ubiquitinated substrates in the proteolytic core of the 20 S CP (7,(11)(12)(13)(14)(15).Decreased 26 S proteasomal activity, resulting in the accumulation of intracellular proteins, has been associated with aging (16, 17) and with pathophysiologic processes, including heart failure, neurodegenerative diseases, and alcohol induced liver injury (18 -20). A number of recent studies have shown that time-limited inhibition of the 26 S proteasome is beneficial as a therapeutic intervention for malignancies, such as multiple myeloma, and in reducing inflammation and cell injury associated with ischemia-reperfusion injury and transplanta...

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Section: Discussionmentioning

confidence: 99%

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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“…During the past two decades, proteasome phosphorylation has often been reported, but it remains unclear whether such modifications actually perturb rates or selectivity of protein degradation. Various subunits have been shown to be phosphorylated in vivo including four of the seven α-subunits that comprise the outer rings of the 20S particle, α7, α3, α2, and α4 (3-7), and two of the six ATPases, Rpt6 (8)(9)(10)(11) and Rpt2 (12), that comprise a ring at the base of the 19S complex. Because these rings lie adjacent to each other, their interactions are very likely to be influenced by phosphorylation and dephosphorylation.…”

mentioning

confidence: 99%

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

Sha

Peth

Goldberg

2011

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

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“…Most recently, it was reported that the proteasomal activity is important to human sperm capacitation, and that PRKA activity regulates the chymotrypsin-like activity of the proteasome during capacitation (Kong et al 2009). Another study revealed that PRKA can positively regulate the proteasomal activity by phosphorylation of Rpt6, one of the six AAA-ATPases in the 19S regulatory subunit of the proteasome (Zhang et al 2007). In addition, we found that bovine sperm expresses both Rpt6 and the proteasome catalytic a-C2 subunit (data not shown).…”

Section: Regulation Of Pi3k In Spermmentioning

confidence: 99%

Protein kinase A and protein kinase Cα/PPP1CC2 play opposing roles in the regulation of phosphatidylinositol 3-kinase activation in bovine sperm

Rotman¹,

Etkovitz²,

Spiegel³

et al. 2010

Reproduction

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In order to acquire fertilization competence, spermatozoa have to undergo biochemical changes in the female reproductive tract, known as capacitation. Signaling pathways that take place during the capacitation process are much investigated issue. However, the role and regulation of phosphatidylinositol 3-kinase (PI3K) in this process are still not clear. Previously, we reported that short-time activation of protein kinase A (PRKA, PKA) leads to PI3K activation and protein kinase Ca (PRKCA, PKCa) inhibition. In the present study, we found that during the capacitation PI3K phosphorylation/activation increases. PI3K activation was PRKA dependent, and down-regulated by PRKCA. PRKCA is found to be highly active at the beginning of the capacitation, conditions in which PI3K is not active. Moreover, inhibition of PRKCA causes significant activation of PI3K. Similar activation of PI3K is seen when the phosphatase PPP1 is blocked suggesting that PPP1 regulates PI3K activity. We found that during the capacitation PRKCA and PPP1CC2 (PP1g2) form a complex, and the two enzymes were degraded during the capacitation, suggesting that this degradation enables the activation of PI3K. This degradation is mediated by PRKA, indicating that in addition to the direct activation of PI3K by PRKA, this kinase can enhance PI3K phosphorylation indirectly by enhancing the degradation and inactivation of PRKCA and PPP1CC2.

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Proteasome Function Is Regulated by Cyclic AMP-dependent Protein Kinase through Phosphorylation of Rpt6

Cited by 186 publications

References 43 publications

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

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

Protein kinase A and protein kinase Cα/PPP1CC2 play opposing roles in the regulation of phosphatidylinositol 3-kinase activation in bovine sperm

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