Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

Melino, Gerry; Cecconi, Francesco; Pelicci, Pier Giuseppe; Mak, Tak W.; Bernassola, Francesca

doi:10.1002/1878-0261.12567

Cited by 14 publications

(11 citation statements)

References 99 publications

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“…At the same time, p63 contributes to the stemness phenotype through its ability to bind to promoters of several components of the Sonic Hedgehog (Hh) signalling pathway and its three ligands-Sonic (SHH), Desert, and Indian (IHH)-and to the Patched (PTCH) receptors that inhibit the G-coupled transmembrane protein Smoothened (SMO); in turn, GLI proteins become transcriptional activators (GLI A ) and induce the expression of Hh target genes, including those involved in stem cell regulation (for example, Bmi1) [69,79]. In this manner, p63 regulates the stemness compartment in breast cancer [69], while inhibiting cell death [80]-a process regulated by p63-triggered proteasomal degradation [81][82][83][84]. Additional mechanisms involving p63 and tumour progression have been evoked in breast cancer [85,86], as well as for other tumours [87,88].…”

Section: Discussionmentioning

confidence: 99%

New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP

et al. 2021

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Breast cancer (BC) is the second leading cause of cancer death in women worldwide, and settings of specific prognostic factors and efficacious therapies are made difficult by phenotypic heterogeneity of BC subtypes. Therefore, there is a current urgent need to define novel predictive genetic predictors that may be useful for stratifying patients with distinct prognostic outcomes. Here, we looked for novel molecular signatures for triple negative breast cancers (TNBCs). By a bioinformatic approach, we identified a panel of genes, whose expression was positively correlated with disease-free survival in TNBC patients, namely IL18R1, CD53, TRIM, Jaw1, LTB, and PTPRCAP, showing specific immune expression profiles linked to survival prediction; most of these genes are indeed expressed in immune cells and are required for productive lymphocyte activation. According to our hypothesis, these genes were not, or poorly, expressed in different TNBC cell lines, derived from either primary breast tumours or metastatic pleural effusions. This conclusion was further supported in vivo, as immuno-histochemical analysis on biopsies of TNBC invasive ductal carcinomas highlighted differential expression of these six genes in cancer cells, as well as in intra- and peri-tumoral infiltrating lymphocytes. Our data open to the possibility that inter-tumour heterogeneity of immune markers might have predictive value; further investigations are recommended in order to establish the real power of cancer-related immune profiles as prognostic factors.

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Section: Discussionmentioning

confidence: 99%

New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP

et al. 2021

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“…Our results indicate that the HECT gene family influences ATP binding, isopeptidase activity, histone binding, protease activity, and numerous molecular and biological processes in tomato. The HECT E3 ubiquitin ligases have been identified to regulate trichome development 54 , leaf senescence 55 , biotic stress 56 , cell growth, proliferation, autophagy, DNA repair, antiviral responses, and many diseases 40 . Our results agree with previous studies and predict extended involvement in the tomato cellular and genetic processes.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of HECT E3 ubiquitin ligase gene family in Solanum lycopersicum

Sharma

Saxena

Negi

2021

Sci Rep

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The E3 ubiquitin ligases have been known to intrigue many researchers to date, due to their heterogenicity and substrate mediation for ubiquitin transfer to the protein. HECT (Homologous to the E6-AP Carboxyl Terminus) E3 ligases are spatially and temporally regulated for substrate specificity, E2 ubiquitin-conjugating enzyme interaction, and chain specificity during ubiquitylation. However, the role of the HECT E3 ubiquitin ligase in plant development and stress responses was rarely explored. We have conducted an in-silico genome-wide analysis to identify and predict the structural and functional aspects of HECT E3 ligase members in tomato. Fourteen members of HECT E3 ligases were identified and analyzed for the physicochemical parameters, phylogenetic relations, structural organizations, tissue-specific gene expression patterns, and protein interaction networks. Our comprehensive analysis revealed the HECT domain conservation throughout the gene family, close evolutionary relationship with different plant species, and active involvement of HECT E3 ubiquitin ligases in tomato plant development and stress responses. We speculate an indispensable biological significance of the HECT gene family through extensive participation in several plant cellular and molecular pathways.

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“…HUWE1 is an E3 ubiquitin ligase harboring HECT domain, which is known to regulate cell proliferation and cell death and, thus, is potentially an important factor in tumorigenesis [33][34][35][36]. However, functional studies have reported discordant effects of changes in HUWE1 activity due to its functionally diverse targets.…”

Section: Discussionmentioning

confidence: 99%

ATG101 Degradation by HUWE1-Mediated Ubiquitination Impairs Autophagy and Reduces Survival in Cancer Cells

Kim

Shin

Kang

et al. 2021

IJMS

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Autophagy is a critical cytoprotective mechanism against stress, which is initiated by the protein kinase Unc-51-like kinase 1 (ULK1) complex. Autophagy plays a role in both inhibiting the progression of diseases and facilitating pathogenesis, so it is critical to elucidate the mechanisms regulating individual components of the autophagy machinery under various conditions. Here, we examined whether ULK1 complex component autophagy-related protein 101 (ATG101) is downregulated via ubiquitination, and whether this in turn suppresses autophagy activity in cancer cells. Knockout of ATG101 in cancer cells using CRISPR resulted in severe growth retardation and lower survival under nutrient starvation. Transfection of mutant ATG101 revealed that the C-terminal region is a key domain of ubiquitination, while co-immunoprecipitation and knockdown experiments revealed that HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1(HUWE1) is a major E3 ubiquitin ligase targeting ATG101. Protein levels of ATG101 was more stable and the related-autophagy activity was higher in HUWE1-depleted cancer cells compared to wild type (WT) controls, indicating that HUWE1-mediated ubiquitination promotes ATG101 degradation. Moreover, enhanced autophagy in HUWE1-depleted cancer cells was reversed by siRNA-mediated ATG101 knockdown. Stable ATG101 level in HUWE1-depleted cells was a strong driver of autophagosome formation similar to upregulation of the known HUWE1 substrate WD repeat domain, phosphoinositide interacting 2 (WIPI2). Cellular survival rates were higher in HUWE1-knockdown cancer cells compared to controls, while concomitant siRNA-mediated ATG101 knockdown tends to increase apoptosis rate. Collectively, these results suggest that HUWE1 normally serves to suppress autophagy by ubiquitinating and triggering degradation of ATG101 and WIPI2, which in turn represses the survival of cancer cells. Accordingly, ATG101-mediated autophagy may play a critical role in overcoming metabolic stress, thereby contributing to the growth, survival, and treatment resistance of certain cancers.

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Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

Cited by 14 publications

References 99 publications

New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP

New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP

Genome-wide analysis of HECT E3 ubiquitin ligase gene family in Solanum lycopersicum

ATG101 Degradation by HUWE1-Mediated Ubiquitination Impairs Autophagy and Reduces Survival in Cancer Cells

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