A centrosomal scaffold shows some self-control

Varadarajan, Ramya; Hammer, John A.; Rusan, Nasser M.

doi:10.1074/jbc.h117.806018

Cited by 4 publications

(8 citation statements)

References 9 publications

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“…Interestingly, expression of portions of PCNT or the PCNT related protein AKAP350 (PCNT related) form cytoplasmic aggregates, which in turn recruit PCM components and nucleate microtubules independent of centrosomes. These studies suggest that regions of PCNT/AKAP350 are required to limit PCM assembly to the proper place and time, however the regulatory mechanisms that impose these limits remain unexplored (Varadarajan, 2017;Kolobova, 2017;Jiang, 2021).…”

Section: Discussionmentioning

confidence: 99%

The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation

Varadarajan

Galletta

Fagerstrom

et al. 2022

Preprint

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Centrosomes are the major microtubule organizing centers (MTOC) of many cells and are composed of centrioles and the pericentriolar material (PCM). Centrosomes are an essential part of diverse cellular processes and require precise regulation of their protein levels. One protein whose levels must be regulated is Pericentrin (PCNT in humans and PLP in Drosophila). Increased PCNT expression and its protein accumulation is linked to clinical conditions including cancer, mental disorders, and ciliopathies. However, the mechanisms by which PCNT levels are regulated remains underexplored. Our previous study (Galletta, 2020) demonstrated that PLP levels are sharply downregulated during early spermatogenesis and this regulation is essential to spatially position PLP on the proximal end of centrioles. We hypothesized that the sharp drop in PLP protein was a result of a rapid protein degradation during the male pre-meiotic G2 phase. In this study we show that the N-terminal region of PLP is required for regulating its levels, which when elevated, extends PLP position distally on centrioles. Consequently, PCM was also mispositioned leading to defects in spermatids. We then performed a targeted screen where we identified the E2 ligases, Rad6 and UbcD1, and the UBR box family E3 ligases, Poe (UBR4) and Hyd (UBR5) as factors that promote PLP degradation in spermatocytes. Collectively, our study suggests that Poe and Hyd directly bind the N-terminus of PLP and target it for degradation, ensuring proper centriole/basal body assembly and male fertility.

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Section: Discussionmentioning

confidence: 99%

The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation

Varadarajan

Galletta

Fagerstrom

et al. 2022

Preprint

Self Cite

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“…66,69,70 It is now known that AKAP9 localizes to the centrosome and the Golgi, which in turn promotes the formation of MT nucleation centers near its C-terminal region by interacting with pericentriolar proteins, involving in MT nucleation to promote MT growth. 22,25 Additionally, AKAP-based signaling platforms have been exploited as the target for subcellular drug-delivery for precision pharmacology, 17,18,71 most notably in the treatment of cancers. 18,67 Furthermore, multiple AKAPs are expressed in many tissues and organs, including the brain and heart 64,65,68 and also the testis as reported here.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, AKAPs, such as AKAP9, are known to be involved in the assembly of the γ‐tubulin ring complex to initiate MT nucleation at the minus (−) slow‐growing end of MTs through its interactions with the centrosome and the Golgi in cells 66,69,70 . It is now known that AKAP9 localizes to the centrosome and the Golgi, which in turn promotes the formation of MT nucleation centers near its C‐terminal region by interacting with pericentriolar proteins, involving in MT nucleation to promote MT growth 22,25 . Additionally, AKAP‐based signaling platforms have been exploited as the target for subcellular drug‐delivery for precision pharmacology, 17,18,71 most notably in the treatment of cancers 18,67 .…”

Section: Discussionmentioning

confidence: 99%

“…22 This protein complex, namely AKAP9/Golgi/centrosome, in turn, facilitates the assembly of γtubulin ring complex (γ-TuRC; MT-nucleating γtubulin ring complex) which is essential to initiate MT nucleation and anchorage. 8,22 Herein, we sought to investigate the stage-specific localization and spatiotemporal expression of AKAP9 in the testis during the epithelial cycle of spermatogenesis in the rat testis. We also examine the role of AKAP9 in regulating MT and actin cytoskeletons in BTB dynamics using the primary cultures of Sertoli cells that mimicked the Sertoli cell BTB in vivo as a study model, and the adjudin animal model.…”

Section: Introductionmentioning

confidence: 99%

“…20,21 More importantly, AKAP9 has been shown to recruit other functional proteins and to interact with cell organelles in particular the Golgi and the centrosome [22][23][24][25] through its Golgi-and centrosome-interacting domains. 22 This protein complex, namely AKAP9/Golgi/centrosome, in turn, facilitates the assembly of γtubulin ring complex (γ-TuRC; MT-nucleating γtubulin ring complex) which is essential to initiate MT nucleation and anchorage. 8,22 Herein, we sought to investigate the stage-specific localization and spatiotemporal expression of AKAP9 in the testis during the epithelial cycle of spermatogenesis in the rat testis.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

AKAP9 supports spermatogenesis through its effects on microtubule and actin cytoskeletons in the rat testis

et al. 2021

The FASEB Journal

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The E3 ligase Poe promotes Pericentrin degradation

Galletta

Varadarajan

Fagerstrom

et al. 2023

MBoC

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Centrosomes are essential parts of diverse cellular processes and precise regulation of the levels of their constituent proteins is critical for their function. One such protein is Pericentrin – PCNT in humans and PLP in Drosophila. Increased PCNT expression and its protein accumulation is linked to clinical conditions including cancer, mental disorders, and ciliopathies. However, the mechanisms by which PCNT levels are regulated remain underexplored. Our previous study (Galletta et al., 2020) demonstrated that PLP levels are sharply downregulated during early spermatogenesis and this regulation is essential to spatially position PLP on the proximal end of centrioles. We hypothesized that the sharp drop in PLP protein was a result of rapid protein degradation during the male germline pre-meiotic G2 phase. Here we show that PLP is subject to ubiquitin-mediated degradation and identify multiple proteins that promote the reduction of PLP levels in spermatocytes, including the UBR box containing E3 ligase Poe (UBR4), which we show binds to PLP. While protein sequences governing post-translational regulation of PLP are not restricted to a single region of the protein, we identify a region that is required for Poe-mediated degradation. Experimentally stabilizing PLP, via internal PLP deletions or loss of Poe, leads to PLP accumulation in spermatocytes, its mispositioning along centrioles, and defects in centriole docking in spermatids.

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A centrosomal scaffold shows some self-control

Cited by 4 publications

References 9 publications

The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation

The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation

AKAP9 supports spermatogenesis through its effects on microtubule and actin cytoskeletons in the rat testis

The E3 ligase Poe promotes Pericentrin degradation

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