Molecular and Cellular Roles of PI31 (PSMF1) Protein in Regulation of Proteasome Function

Li, Xiaohua; Thompson, David C.; Kumar, Brajesh; DeMartino, George N.

doi:10.1074/jbc.m114.561183

Cited by 65 publications

(87 citation statements)

References 55 publications

(98 reference statements)

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“…There are conflicting reports as to the effect of PI31 on proteasome function. The original paper showed that mammalian PI31 inhibits 20S CP activity in vitro, but other reports indicate that PI31 cooperates with the proteasome in protein degradation in fruit flies (20,(24)(25)(26).…”

Section: Fub1 Is Associated Mainly With the 20s Cpmentioning

confidence: 99%

“…Furthermore, when PI31 was overexpressed in cells, the formation of the immunoproteasome, which is one of the CP subtypes, was attenuated, and thus processing of an immunoproteasome-dependent epitope was impaired (23). In contrast, recent studies have shown that the Drosophila melanogaster PI31 homolog (DmPI31) activated the 26S proteasome in vitro and that knockdown of DmPI31 in flies compromised protein degradation by the proteasome (24,25), while mammalian PI31 had no effect on the in vitro activity of the 26S proteasome (26). In view of these conflicting findings, the physiological role and the mechanism of action of PI31 in proteasome-mediated protein degradation remain enigmatic.…”

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confidence: 98%

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N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

Yashiroda

Toda

Otsu

et al. 2015

Molecular and Cellular Biology

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The proteasome core particle (CP) is a conserved protease complex that is formed by the stacking of two outer ␣-rings and two inner ␤-rings. The ␣-ring is a heteroheptameric ring of subunits ␣1 to ␣7 and acts as a gate that restricts entry of substrate proteins into the catalytic cavity formed by the two abutting ␤-rings. The 31-kDa proteasome inhibitor (PI31) was originally identified as a protein that binds to the CP and inhibits CP activity in vitro, but accumulating evidence indicates that PI31 is required for physiological proteasome activity. To clarify the in vivo role of PI31, we examined the Saccharomyces cerevisiae PI31 ortholog Fub1. Fub1 was essential in a situation where the CP assembly chaperone Pba4 was deleted. The lethality of ⌬fub1 ⌬pba4 was suppressed by deletion of the N terminus of ␣7 (␣7⌬N), which led to the partial activation of the CP. However, deletion of the N terminus of ␣3, which activates the CP more efficiently than ␣7⌬N by gate opening, did not suppress ⌬fub1 ⌬pba4 lethality. These results suggest that the ␣7 N terminus has a role in CP activation different from that of the ␣3 N terminus and that the role of Fub1 antagonizes a specific function of the ␣7 N terminus. The 26S proteasome is a multicatalytic protease complex conserved in eukaryotes (1). Its main function is to serve as a selective and regulated mechanism for intracellular protein degradation, mainly in a ubiquitin-dependent manner. The 26S proteasome consists of one 20S core particle (CP) and one or two 19S regulatory particles (RPs) attached to the CP.The CP exerts proteolytic activity and is made up of four axially stacked heteroheptameric rings: two outer ␣-rings formed by ␣1 to ␣7 and two inner ␤-rings formed by ␤1 to ␤7. Of the seven ␤-subunits, only ␤1, ␤2, and ␤5 have proteolytic activities. The archaebacterium Thermoplasma acidophilum has a prototype of the CP that consists of a single type of ␣-and ␤-subunit, with all the ␤-subunits being catalytically active. Another difference between archaeal and eukaryotic CPs is the structure of the ␣-rings. Whereas archaeal CPs have a disordered gate that is permeable to peptide substrates, the eukaryotic ␣-ring of the CP is primarily in a closed state because the N termini of ␣1, ␣2, ␣3 (Pre9), ␣6, and ␣7 project into the opening of the ␣-ring (2-4). Therefore, the activity of the eukaryotic CP is basically latent. Of the ␣-subunits, ␣3 is supposed to be most important because the N terminus of ␣3 projects directly across the pseudo 7-fold symmetry axis. In addition, its deletion (␣3⌬N) causes disorder of the N termini of ␣1, ␣5, and ␣7, leading to an open state of ␣-rings (5). In vivo, binding of CP activators, such as the RPs, opens the closed ␣-ring (6, 7).The CP is assembled with the aid of various proteasome-dedicated chaperones in mammals and Saccharomyces cerevisiae (8-13). The assembly of CPs begins with the formation of the ␣-ring, assisted by the heterodimeric complexes PAC1-PAC2/Pba1-Pba2 and PAC3-PAC4/Pba3-Pba4 in mammals/yeast. After the formation of the ␣-...

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Section: Fub1 Is Associated Mainly With the 20s Cpmentioning

confidence: 99%

mentioning

confidence: 98%

N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

Yashiroda

Toda

Otsu

et al. 2015

Molecular and Cellular Biology

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“…The proteasome activator 28 (PA28) family, which comprises the heptameric PA28␣/␤ and PA28␥ complexes, and the proteasome activator 200 (PA200), however, function in an ubiquitin-and ATP-independent manner unless they assemble into so-called hybrid proteasome complexes that also contain one 19S regulator attached to one side of the 20S core (3, 6 -9). In addition to these three activators, another regulator (PI31) of the 20S complex has been identified but its functions for proteolysis remain obscure (10).…”

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confidence: 99%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

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The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28␣␤, PA28␥, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28␥ and PA200 to 20S and 26S proteasomes within 2-6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28␥ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of ␤5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28␥ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28␥ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis.The proteasome, one of the main proteolytic systems of the cell, is essential for maintenance of protein homeostasis and thus of cellular functions. The proteolytic activity of this multicatalytic protease resides inside the 20S core particle, built of four stacked rings of seven ␣ and ␤ subunits with ␣ 7

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“…In this study, we identified the very same dynein light chain proteins as direct binding partners of the conserved proteasome regulator PI31 ("Proteasome Inhibitor of 31kD"). Because PI31 binds directly to proteasomes, the ability of PI31 to also bind to DYNLL1/2 proteins suggests that PI31 serves as an adapter to couple proteasomes via dynein light chain proteins to microtubule-based motors (Bader et al, 2011;Cho-Park and Steller, 2013;Chu-Ping et al, 1992;Li et al, 2014;McCutchen-Maloney et al, 2000;Yashiroda et al, 2015;Zaiss et al, 1999). In support of this idea, inactivation of PI31 disrupted proteasome movement in Drosophila neurons and caused functional and structural neuronal defects.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the PI31 ortholog in yeast, Fub1, is required to alleviate proteotoxic stress (Yashiroda et al, 2015). However, studies in cultured HEK293 mammalian cells have failed to reveal a clear effect of PI31 for proteasome activity, suggesting that PI31 function may be different in different cell types and systems (Li et al, 2014).…”

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confidence: 99%

PI31 is an adaptor protein for proteasome transport in axons and required for synaptic development and function

Jones

Minis

et al. 2018

Preprint

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Degradation of proteins by the ubiquitin-proteasome pathway (UPP) is critical for the maintenance of protein homeostasis, cell function and survival. While all cells require regulated protein degradation, nerve cells face unique challenges as their highly complex structure and large intracellular space requires special mechanisms to allocate proteasomes to appropriate sub-cellular compartments where protein breakdown occurs. Here we show that the conserved proteasome-binding protein PI31 mediates axonal transport of proteasomes. PI31 binds directly to both proteasomes and dynein light chain LC8-type proteins (DYNLL1/2) and thereby promotes the formation of DYNLL1-PI31-proteasome complexes both in vivo and in vitro. Inactivation of PI31 inhibits proteasome motility in axons of Drosophila neurons, similar to ablation of dDYNLL1/ctp, and it disrupts synaptic protein homeostasis, structure and function. These results indicate that PI31 serves a critical function as an adapter protein to transport proteasomes to the periphery of neurons via microtubule-based motors. Because mutations affecting the activity of PI31 are associated with human neurodegenerative diseases, it is possible that impairment of PI31-mediated axonal transport is the root cause of these disorders.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Molecular and Cellular Roles of PI31 (PSMF1) Protein in Regulation of Proteasome Function

Cited by 65 publications

References 55 publications

N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

PI31 is an adaptor protein for proteasome transport in axons and required for synaptic development and function

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