Microtubular TRIM36 E3 Ubiquitin Ligase in Embryonic Development and Spermatogenesis

TRIM36 is a member of the tripartite motif (TRIM) family of RING-containing proteins, also known as Haprin, which was first discovered for its abundance in testis and found to be implicated in the spermatozoa acrosome reaction. TRIM36 is a microtubule-associated E3 ubiquitin ligase that plays a role in cytoskeletal organization, and according to data gathered in different species, coordinates growth speed and stability, acting on the microtubules’ plus end, and impacting on cell cycle progression. TRIM36 is also crucial for early developmental processes, in Xenopus, where it is needed for dorso-ventral axis formation, but also in humans as bi-allelic mutations in the TRIM36 gene cause a form of severe neural tube closure defect, called anencephaly. Here, we review TRIM36-related mechanisms implicated in such composite physiological and pathological processes.

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The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

Scientific Reports ◽

10.1038/s41598-020-57762-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

D. Larrieu ◽

M. Brunet ◽

C. Vargas ◽

N. Hanoun ◽

L. Ligat ◽

...

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

E3 Ubiquitin Ligase ◽

Chromosome Stability ◽

Cycle Progression

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The human GID complex engages two independent modules for substrate recruitment

10.1101/2021.04.07.438752 ◽

2021 ◽

Author(s):

Matthias Peter ◽

Weaam I. Mohamed ◽

Sophia L. Park ◽

Julius Rabl ◽

Alexander Leitner ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Binding Sites ◽

Cell Cycle Progression ◽

Substrate Recognition ◽

E3 Ubiquitin Ligase ◽

Biological Processes ◽

Cycle Progression ◽

Cryo Electron Microscopy ◽

Biochemical Assays

The human GID (hGID) complex is an evolutionary conserved E3 ubiquitin ligase regulating diverse biological processes including glucose metabolism and cell cycle progression. However, the biochemical function and substrate recognition of the multi-subunit complex remains poorly understood. While the yeast GID complex recognizes Pro/N-end rule substrates via yeast Gid4, the human GID complex requires a WDR26/Gid7-dependent module to trigger proteasomal degradation of mammalian HBP1. Here, using biochemical assays, crosslinking-mass spectrometry and cryo-electron microscopy, we show that hGID unexpectedly engages two distinct modules for substrate recruitment, dependent on either WDR26 or GID4. WDR26 together with RanBP9 cooperate to ubiquitinate HBP1 in vitro, while GID4 is dispensable for this reaction. In contrast, GID4 functions as an adaptor for the substrate ZMYND19, which surprisingly lacks a Pro/N-end rule degron. GID4 substrate binding and ligase activity is regulated by ARMC8 alpha, while the shorter ARMC8 beta; isoform assembles into a stable hGID complex that is unable to recruit GID4. Cryo-EM reconstructions of these hGID complexes reveal the localization of WDR26 within a ring-like, tetrameric architecture and suggest that GID4 and WDR26/Gid7 utilize different, non-overlapping binding sites. Together, these data advance our mechanistic understanding of how the hGID complex recruits cognate substrates and provide insights into the regulation of its ligase activity.

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Cellular functions of the BRCA tumour-suppressor proteins

Biochemical Society Transactions ◽

10.1042/bst0340633 ◽

2006 ◽

Vol 34 (5) ◽

pp. 633-645 ◽

Cited By ~ 129

Author(s):

S.J. Boulton

Keyword(s):

Ubiquitin Ligase ◽

Genome Stability ◽

Cell Cycle Progression ◽

Sex Chromosome ◽

Cellular Level ◽

Cellular Functions ◽

Brca1 And Brca2 ◽

Cycle Progression ◽

Future Directions ◽

Meiotic Sex Chromosome Inactivation

Inherited germline mutations in either BRCA1 or BRCA2 confer a significant lifetime risk of developing breast or ovarian cancer. Defining how these two genes function at the cellular level is essential for understanding their role in tumour suppression. Although BRCA1 and BRCA2 were independently cloned over 10 years ago, it is only in the last few years that significant progress has been made towards understanding their function in cells. It is now widely accepted that both genes play critical roles in the maintenance of genome stability. Evidence implicates BRCA2 as an integral component of the homologous recombination machinery, whereas BRCA1 is an E3 ubiquitin ligase that has an impact on DNA repair, transcriptional regulation, cell-cycle progression and meiotic sex chromosome inactivation. In this article, I will review the most recent advances and provide a perspective of potential future directions in this field.

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The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development.

Journal of Cell Science ◽

10.1242/jcs.083006 ◽

2010 ◽

Vol 123 (22) ◽

pp. e1-e1

Author(s):

J. Merlet ◽

J. Burger ◽

N. Tavernier ◽

B. Richaudeau ◽

J.-E. Gomes ◽

...

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Cycle Progression ◽

C Elegans

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WW domain–mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.003781 ◽

2018 ◽

Vol 293 (43) ◽

pp. 16697-16708 ◽

Cited By ~ 6

Author(s):

Weiyi Yao ◽

Zelin Shan ◽

Aihong Gu ◽

Minjie Fu ◽

Zhifeng Shi ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Regulatory Mechanism ◽

Cycle Progression ◽

Hect Domain ◽

Ww Domain ◽

Ww Domains ◽

E3 Ligases ◽

Regulation Of Cell Cycle ◽

Py Motif

The Nedd4 family E3 ligases Itch and WWP1/2 play crucial roles in the regulation of cell cycle progression and apoptosis and are closely correlated with cancer development and metastasis. It has been recently shown that the ligase activities of Itch and WWP1/2 are tightly regulated, with the HECT domain sequestered intramolecularly by a linker region connecting WW2 and WW3. Here, we show that a similar autoinhibitory mechanism is utilized by the Drosophila ortholog of Itch and WWP1/2, Suppressor of Deltex (Su(dx)). We show that Su(dx) adopts an inactive steady state with the WW domain region interacting with the HECT domain. We demonstrate that both the linker and preceding WW2 are required for the efficient binding and regulation of Su(dx) HECT. Recruiting the multiple-PY motif–containing adaptor dNdfip via WW domains relieves the inhibitory state of Su(dx) and leads to substrate (e.g. Notch) ubiquitination. Our study demonstrates an evolutionarily conservative mechanism governing the regulation and activation of some Nedd4 family E3 ligases. Our results also suggest a dual regulatory mechanism for specific Notch down-regulation via dNdfip–Su(dx)–mediated Notch ubiquitination.

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E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

International Journal of Molecular Sciences ◽

10.3390/ijms21228515 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8515

Author(s):

Manon Brunet ◽

Claire Vargas ◽

Dorian Larrieu ◽

Jérôme Torrisani ◽

Marlène Dufresne

Keyword(s):

Thyroid Hormone ◽

Ubiquitin Ligase ◽

Hormone Receptor ◽

Cell Cycle Progression ◽

Thyroid Hormone Receptor ◽

E3 Ubiquitin Ligase ◽

Autism Spectrum ◽

Causative Gene ◽

Interacting Protein ◽

C Terminus

The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.

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TORC1 signaling exerts spatial control over microtubule dynamics by promoting nuclear export of Stu2

The Journal of Cell Biology ◽

10.1083/jcb.201606080 ◽

2017 ◽

Vol 216 (11) ◽

pp. 3471-3484 ◽

Cited By ~ 5

Author(s):

Babet van der Vaart ◽

Josef Fischböck ◽

Christine Mieck ◽

Peter Pichler ◽

Karl Mechtler ◽

...

Keyword(s):

Nuclear Export ◽

Cell Cycle Progression ◽

Nuclear Export Signal ◽

Nuclear Accumulation ◽

Yeast Saccharomyces Cerevisiae ◽

Cycle Progression ◽

Cytoskeletal Organization ◽

Spindle Positioning ◽

Cellular Processes ◽

Export Signal

The target of rapamycin complex 1 (TORC1) is a highly conserved multiprotein complex that functions in many cellular processes, including cell growth and cell cycle progression. In this study, we define a novel role for TORC1 as a critical regulator of nuclear microtubule (MT) dynamics in the budding yeast Saccharomyces cerevisiae. This activity requires interactions between EB1 and CLIP-170 plus end–tracking protein (+TIP) family members with the TORC1 subunit Kog1/Raptor, which in turn allow the TORC1 proximal kinase Sch9/S6K1 to regulate the MT polymerase Stu2/XMAP215. Sch9-dependent phosphorylation of Stu2 adjacent to a nuclear export signal prevents nuclear accumulation of Stu2 before cells enter mitosis. Mutants impaired in +TIP–TORC1 interactions or Stu2 nuclear export show increased nuclear but not cytoplasmic MT length and display nuclear fusion, spindle positioning, and elongation kinetics defects. Our results reveal key mechanisms by which TORC1 signaling controls Stu2 localization and thereby contributes to proper MT cytoskeletal organization in interphase and mitosis.

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Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin A-specific role in p27KIP1 degradation

10.1101/2020.10.08.329599 ◽

2020 ◽

Author(s):

Marco Salamina ◽

Bailey C. Montefiore ◽

Mengxi Liu ◽

Daniel J. Wood ◽

Richard Heath ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Direct Interaction ◽

Cyclin A ◽

Cyclin B ◽

Regulatory Subunit ◽

Checkpoint Control ◽

Cycle Progression ◽

Structural Mechanism ◽

Fine Tune

AbstractThe SCFSKP2 ubiquitin ligase relieves G1 checkpoint control of CDK-cyclin complexes by promoting p27KIP1 degradation. We describe reconstitution of stable complexes containing SKP1-SKP2 and CDK1-cyclin B or CDK2-cyclin A/E, mediated by the CDK regulatory subunit CKS1. We further show that a direct interaction between a SKP2 N-terminal motif and cyclin A can stabilize SKP1-SKP2-CDK2-cyclin A complexes in the absence of CKS1. We identify the SKP2 binding site on cyclin A and demonstrate the site is not present in cyclin B or cyclin E. This site is distinct from but overlapping with features that mediate binding of p27KIP1 and other G1 cyclin regulators to cyclin A. We propose that the capacity of SKP2 to engage with CDK2-cyclin A by more than one structural mechanism provides a way to fine tune the degradation of p27KIP1 and distinguishes cyclin A from other G1 cyclins to ensure orderly cell cycle progression.

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The E3 ubiquitin ligase HECTD1 contributes to cell cycle progression through an effect on mitosis

10.1101/2021.12.17.473173 ◽

2021 ◽

Author(s):

Natalie Vaughan ◽

Nico Scholz ◽

Catherine Lindon ◽

Julien D, F Licchesi

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Spindle Assembly Checkpoint ◽

Time Lapse ◽

Ubiquitin Chain ◽

Cycle Progression ◽

Anaphase Onset ◽

Ubiquitin Ligase Activity ◽

Complex Protein

Mechanistic studies of how protein ubiquitylation regulates the cell cycle, in particular during mitosis, has provided unique insights which have contributed to the emergence of the Ubiquitin code. In contrast to RING E3 ubiquitin ligases such as the APC/c ligase complex, the contribution of other E3 ligase families during cell cycle progression remains less well understood. Similarly, the contribution of ubiquitin chain types beyond homotypic K48 chains in S-phase or branched K11/K48 chains assembled by APC/c during mitosis, also remains to be fully determined. Our recent findings that HECTD1 ubiquitin ligase activity assembles branched K29/K48 ubiquitin linkages prompted us to evaluate its function during the cell cycle. We used transient knockdown and genetic knockout to show that HECTD1 depletion in HEK293T and HeLa cells decreases cell proliferation and we established that this is mediated through loss of its ubiquitin ligase activity. Interestingly, we found that HECTD1 depletion increases the proportion of cells with aligned chromosomes (Prometa/Metaphase). We confirmed this molecularly using phospho-Histone H3 (Ser28) as a marker of mitosis. Time-lapse microscopy of NEBD to anaphase onset established that HECTD1-depleted cells take on average longer to go through mitosis. To explore the mechanisms involved, we used proteomics to explore the endogenous HECTD1 interactome in mitosis and validated the Mitosis Checkpoint Complex protein BUB3 as a novel HECTD1 interactor. In line with this, we found that HECTD1 depletion reduces the activity of the Spindle Assembly Checkpoint. Overall, our data suggests a novel role for HECTD1 ubiquitin ligase activity in mitosis.

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