Parkin: a multifaceted ubiquitin ligase

2006 ◽  
Vol 34 (5) ◽  
pp. 749-753 ◽  
Author(s):  
D.J. Moore
Keyword(s):  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Autosomal Recessive ◽  
E3 Ubiquitin Ligase ◽  
Gene Products ◽  
Biochemical Pathway ◽  
Leucine Rich Repeat ◽  
Parkin Gene ◽  
Protein Substrates ◽  
Phosphatase And Tensin Homologue

Mutations in the parkin gene are a common cause of autosomal recessive early-onset parkinsonism. Parkin functions as an E3 ubiquitin ligase where it can polyubiquitinate a number of its protein substrates, thus targeting them for degradation by the 26 S proteasomal complex. Recent studies have demonstrated that alternative modes of parkin-mediated ubiquitination may serve other non-degradative regulatory roles. In addition, parkin appears to function as a multipurpose neuroprotectant in a number of toxic paradigms. Coupled with these observations, parkin may integrate other gene products associated with parkinsonism, including α-synuclein, LRRK2 (leucine-rich repeat kinase 2), DJ-1 and PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced putative kinase 1], into a common biochemical pathway of potential relevance to disease pathogenesis. Parkin therefore represents a unique multifaceted ubiquitin ligase consistent with an important housekeeping role in maintaining the integrity or survival of dopaminergic neurons.

scholarly journals Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Juan Tang ◽  
Sha Tu ◽  
Guoxin Lin ◽  
Hui Guo ◽  
Chengkai Yan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Lethal Dose ◽  
E3 Ubiquitin Ligase ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Leucine Rich Repeat ◽  
Nlrp3 Inflammasome Activation ◽  
Repeat Domain ◽  
Nlrp3 Inflammasomes ◽  
Lrr Domain

Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3–dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.

scholarly journals A serine in the first transmembrane domain of the human E3 ubiquitin ligase MARCH9 is critical for down-regulation of its protein substrates

2018 ◽  
Vol 294 (7) ◽  
pp. 2470-2485 ◽  
Author(s):  
Cyrus Tan ◽  
Eamon F. X. Byrne ◽  
Casey Ah-Cann ◽  
Melissa J. Call ◽  
Matthew E. Call
Keyword(s):  
Ubiquitin Ligase ◽  
Transmembrane Domain ◽  
E3 Ubiquitin Ligase ◽  
Down Regulation ◽  
Protein Substrates

scholarly journals SUSA2 is an F-box protein required for autoimmunity mediated by paired NLRs SOC3-CHS1 and SOC3-TN2

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wanwan Liang ◽  
Meixuezi Tong ◽  
Xin Li
Keyword(s):  
Ubiquitin Ligase ◽  
Higher Plants ◽  
Interaction Analysis ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Pairwise Interaction ◽  
Leucine Rich Repeat ◽  
Scf Complex ◽  
F Box Protein ◽  
Effector Recognition

Abstract Both higher plants and mammals rely on nucleotide-binding leucine-rich repeat (NLR) immune receptors to detect pathogens and initiate immunity. Upon effector recognition, plant NLRs oligomerize for defense activation, the mechanism of which is poorly understood. We previously showed that disruption of the E3 ligase, Senescence-Associated E3 Ubiquitin Ligase 1 (SAUL1) leads to the activation of the NLR SOC3. Here, we report the identification of suppressor of saul1 2 (susa2) and susa3 from the saul1-1 suppressor screen. Pairwise interaction analysis suggests that both SUSA proteins interact with components of an SCFSUSA2 E3 ligase complex as well as CHS1 or TN2, truncated NLRs that pair with SOC3. susa2-2 only suppresses the autoimmunity mediated by either CHS1 or TN2, suggesting its specific involvement in SOC3-mediated immunity. In summary, our study indicates links between plant NLRs and an SCF complex that may enable ubiquitination and degradation of unknown downstream components to activate defense.

scholarly journals A Novel Degron-mediated Degradation of the RTG Pathway Regulator, Mks1p, by SCFGrr1

2005 ◽  
Vol 16 (10) ◽  
pp. 4893-4904 ◽  
Author(s):  
Zhengchang Liu ◽  
Mário Spírek ◽  
Janet Thornton ◽  
Ronald A. Butow
Keyword(s):  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Positive Charge ◽  
E3 Ubiquitin Ligase ◽  
Retrograde Signaling ◽  
Yeast Cells ◽  
Leucine Rich Repeat ◽  
Negative Regulators ◽  
Acidic Domain ◽  
Lrr Domain

Yeast cells respond to mitochondrial dysfunction by altering the expression of a subset of nuclear genes, a process known as retrograde signaling (RS). RS terminates with two transcription factors, Rtg1p and Rtg3p. One positive regulator, Rtg2p, and four negative regulators, Lst8p, Mks1p, and the redundant 14-3-3 proteins, Bmh1p and Bmh2p, control RS upstream of Rtg1/3p. Mks1p is negatively regulated by binding to Rtg2p and positively regulated when bound to Bmh1/2p. Here we report that Grr1p, a component of the SCFGrr1 E3 ubiquitin ligase, modulates RS by affecting Mks1p levels. Grr1p polyubiquitinates Mks1p not bound to either Rtg2p or to Bmh1/2p, targeting it for degradation. An acidic domain region of Mks1p constitutes the portable Mks1p degron sequence. We have isolated dominant mutations in Grr1p leading to increased Mks1p degradation. These mutations result in a gain of positive charge on the concave surface of the leucine rich repeat (LRR) domain of Grr1p, the proposed substrate binding site. We propose that Mks1p is a central player of RS and is acted upon by multiple regulators of the pathway.

scholarly journals Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein

2020 ◽  
Vol 6 (18) ◽  
pp. eaba1193 ◽  
Author(s):  
Eunna Chung ◽  
Youngsil Choi ◽  
Jiae Park ◽  
Wonheum Nah ◽  
Jaehyung Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Intracellular Delivery ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Body Formation ◽  
Enhanced Solubility ◽  
A Cell

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, Lewy body formation, and loss of dopaminergic neurons. Parkin, an E3 ubiquitin ligase, is thought to inhibit PD progression by removing damaged mitochondria and suppressing the accumulation of α-synuclein and other protein aggregates. The present study describes a protein-based therapy for PD enabled by the development of a cell-permeable Parkin protein (iCP-Parkin) with enhanced solubility and optimized intracellular delivery. iCP-Parkin recovered damaged mitochondria by promoting mitophagy and mitochondrial biogenesis and suppressed toxic accumulations of α-synuclein in cells and animals. Last, iCP-Parkin prevented and reversed declines in tyrosine hydroxylase and dopamine expression concomitant with improved motor function induced by mitochondrial poisons or enforced α-synuclein expression. These results point to common, therapeutically tractable features in PD pathophysiology, and suggest that motor deficits in PD may be reversed, thus providing opportunities for therapeutic intervention after the onset of motor symptoms.

scholarly journals The Arabidopsis Mutant sleepy1gar2-1 Protein Promotes Plant Growth by Increasing the Affinity of the SCFSLY1 E3 Ubiquitin Ligase for DELLA Protein Substrates

2004 ◽  
Vol 16 (6) ◽  
pp. 1406-1418 ◽  
Author(s):  
Xiangdong Fu ◽  
Donald E. Richards ◽  
Barbara Fleck ◽  
Daoxin Xie ◽  
Nicolas Burton ◽  
...  
Keyword(s):  
Plant Growth ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Della Protein ◽  
Protein Substrates ◽  
Arabidopsis Mutant

Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family

2014 ◽  
Vol 133 (8) ◽  
pp. 975-984 ◽  
Author(s):  
Asif Mir ◽  
Kumudesh Sritharan ◽  
Kirti Mittal ◽  
Nasim Vasli ◽  
Carolina Araujo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Ubiquitin Ligase ◽  
Autosomal Recessive ◽  
E3 Ubiquitin Ligase ◽  
Pakistani Family

scholarly journals The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6

2020 ◽  
Vol 477 (2) ◽  
pp. 541-555 ◽  
Author(s):  
Nicola A. Scott ◽  
Laura J. Sharpe ◽  
Isabelle M. Capell-Hattam ◽  
Samuel J. Gullo ◽  
Winnie Luu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Branch Point ◽  
Cholesterol Synthesis ◽  
E3 Ubiquitin Ligase ◽  
Biochemical Pathway ◽  
Lanosterol Synthase ◽  
Rate Limiting ◽  
Fine Tune

Cholesterol synthesis is a tightly controlled pathway, with over 20 enzymes involved. Each of these enzymes can be distinctly regulated, helping to fine-tune the production of cholesterol and its functional intermediates. Several enzymes are degraded in response to increased sterol levels, whilst others remain stable. We hypothesised that an enzyme at a key branch point in the pathway, lanosterol 14α-demethylase (LDM) may be post-translationally regulated. Here, we show that the preceding enzyme, lanosterol synthase is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols. However, the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. Our work highlights MARCH6 as the first example of an E3 ubiquitin ligase that targets multiple steps in a biochemical pathway and indicates new facets in the control of cholesterol synthesis.

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