Regulation of the autophagic PI3KC3 complex by laforin/malin E3-ubiquitin ligase, two proteins involved in Lafora disease

Sánchez‐Martín, Pablo; Lahuerta, Marcos; Viana, Rosa; Knecht, Erwin; Sanz, Pascual

doi:10.1016/j.bbamcr.2019.118613

Cited by 20 publications

(17 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, it has also been described that laforin interacts physically with the chaperone Hsp70 and helps to decrease the toxicity of the unfolded proteins [177]. Therefore, all these results suggest a possible role of the laforin-malin complex in regulating cellular proteostasis [134,170,[173][174][175][176].…”

Section: Lafora Disease (Ld)mentioning

confidence: 76%

“…However, these mechanisms are unsuccessful in disposing of the LBs and become deteriorated. In fact, it has been suggested that in the absence of laforin or malin there is a decrease in the activity of proteasomes [173,174] and an impairment in autophagy, which likely occurs at the initial step of autophagosome formation [134,170,175,176]. As a consequence, activation of the unfolded protein response pathway proceeds, which eventually leads to increased endoplasmic reticulum stress [171,174].…”

Section: Lafora Disease (Ld)mentioning

confidence: 99%

See 1 more Smart Citation

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

et al. 2020

Self Cite

View full text Add to dashboard Cite

Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich's ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies.

show abstract

Section: Lafora Disease (Ld)mentioning

confidence: 76%

Section: Lafora Disease (Ld)mentioning

confidence: 99%

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, the N-terminal 640 residues (NTD) of FIP200, shaping like a letter C with the presence of ATG13, has an intimate interaction with C-terminal IDR of ATG13 and C-terminal early autophagy targeting/tethering (EAT) domain of ULK1, ensuring the successful initiation of autophagy ( Shi et al, 2020 ). Following the activation of ULK1 complex, the class III phosphatidylinositol 3-kinase (PI3KC3) complex, which consists of vacuolar protein sorting 34 (VPS34, also known as PI3KC3), ATG14, the activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1), and the scaffold protein Beclin-1, generates phosphatidylinositol 3-phosphate (PI3P) at an endoplasmic reticulum (ER) subdomain named omegasome ( Young et al, 2019 ; Sanchez-Martin et al, 2020 ). Subsequently, PI3P recruits certain effector proteins, including WIPIs (WD repeat domain phosphoinositide-interacting proteins) ( Figure 2B ), which can bind ATG16L1 ( Bakula et al, 2017 ).…”

Section: Overview Of Autophagymentioning

confidence: 99%

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Tang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

show abstract

“…In the initiation step, ULK1 activity is either promoted by TRIM32 through K63 chain ubiquitination (Di Rienzo et al, 2019), or silenced by NEDD4L through unusual K27/29 ubiquitin-dependent degradation following few hours of induction, as a regulatory mechanism to avoid damages from overactivity (Nazio et al, 2016). Promoting phagophore formation, Malin (in complex with Laforin) and CHN-1 (the Caenorhabditis elegans homologous of CHIP) activates the PI3KC3 complex, trough K63-ubiquitination of Beclin1 and several regulators (Sanchez-Martin et al, 2020) and VPS34 (Liu et al, 2018), respectively. On the contrary, RNF216 acts as a negative regulator of autophagy by targeting Beclin1 to degradation (Xu et al, 2014).…”

Section: Emerging Roles Of E3 Ligases In the Control Of Autophagymentioning

confidence: 99%

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Lescouzères

Bomont

2020

Front. Physiol.

View full text Add to dashboard Cite

Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ∼800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

show abstract

Regulation of the autophagic PI3KC3 complex by laforin/malin E3-ubiquitin ligase, two proteins involved in Lafora disease

Cited by 20 publications

References 42 publications

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Contact Info

Product

Resources

About