Ubiquitin-Dependent And Independent Signals In Selective Autophagy

Khaminets, Aliaksandr; Behl, Christian; Đikić, Ivan

doi:10.1016/j.tcb.2015.08.010

Cited by 592 publications

(552 citation statements)

References 121 publications

(159 reference statements)

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“…6C-E). This includes the RUBCN gene (named KIAA0226 in FasterDB and Exon Ontology) that codes for a major autophagy inhibitor interacting with beclin 1 (BECN1) and the WDFY3 gene (also known as ALFY) that codes for an important adaptor protein for selective autophagy interacting with MAP1LC3B (also known as LC3B), SQSTM1 (also known as p62), and GABARAPs (Matsunaga et al 2009;Isakson et al 2013;Lamb et al 2013;Baixauli et al 2014;Wild et al 2014;Khaminets et al 2016;Ktistakis and Tooze 2016).…”

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological-or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information. [Supplemental material is available for this article.]Alternative splicing is a major step in the gene expression process leading to the production of different transcripts with different exon content (or alternative splicing variants) from one single gene. This mechanism is the rule, as 95% of human genes produce at least two splicing variants (Nilsen and Graveley 2010;de Klerk and 't Hoen 2015;Lee and Rio 2015). Alternative splicing decisions rely on splicing factors binding on pre-mRNA molecules more or less close to splicing sites and regulating their recognition by the spliceosome (Lee and Rio 2015). Other mechanisms, including usage of alternative promoters and alternative polyadenylation sites, also increase the diversity of transcripts and drive both quantitative and qualitative effects (Tian and Manley 2013;de Klerk and 't Hoen 2015). Indeed, alternative promoters and alternative polyadenylation sites can impact mRNA 5 ′ -and 3 ′ -untranslated regions, which can have consequences on transcript stability or translation (Tian and Manley 2013;de Klerk and 't Hoen 2015). In addition, alternative splicing can lead to the biogenesis of nonproductive mRNAs degraded by the nonsense-mediated mRNA decay pathway (Hamid and Makeyev 2014). These mechanisms can also change the gene coding sequence. Alternative promoters and alternative polyadenylation sites can change protein N-and C-terminal domains, respec...

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Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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“…Excessive protein aggregation and the accumulation of defective protein complexes (e.g., ribosomes and proteasomes) and organelles (e.g., chloroplasts and mitochondria) often engage autophagy (Li and Vierstra, 2012;Khaminets et al, 2016;Marshall et al, 2015). These damaged structures are encapsulated into cytoplasmic vesicles and delivered to the vacuole/lysosome for breakdown, in many cases using ubiquitylation as a signal.…”

Section: Introductionmentioning

confidence: 99%

The Proteasome Stress Regulon Is Controlled by a Pair of NAC Transcription Factors in Arabidopsis

et al. 2016

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Proteotoxic stress, which is generated by the accumulation of unfolded or aberrant proteins due to environmental or cellular perturbations, can be mitigated by several mechanisms, including activation of the unfolded protein response and coordinated increases in protein chaperones and activities that direct proteolysis, such as the 26S proteasome. Using RNA-seq analyses combined with chemical inhibitors or mutants that induce proteotoxic stress by impairing 26S proteasome capacity, we defined the transcriptional network that responds to this stress in Arabidopsis thaliana. This network includes genes encoding core and assembly factors needed to build the complete 26S particle, alternative proteasome capping factors, enzymes involved in protein ubiquitylation/deubiquitylation and cellular detoxification, protein chaperones, autophagy components, and various transcriptional regulators. Many loci in this proteasome-stress regulon contain a consensus cis-element upstream of the transcription start site, which was previously identified as a binding site for the NAM/ATAF1/CUC2 78 (NAC78) transcription factor. Double mutants disrupting NAC78 and its closest relative NAC53 are compromised in the activation of this regulon and notably are strongly hypersensitive to the proteasome inhibitors MG132 and bortezomib. Given that NAC53 and NAC78 homo-and heterodimerize, we propose that they work as a pair in activating the expression of numerous factors that help plants survive proteotoxic stress and thus play a central regulatory role in maintaining protein homeostasis.

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“…(9). Ub-dependent as well as Ub-independent tags on the cargo serve as recognition signals for selective sequestration by the autophagic machinery (10). Also, autophagy of proteasomes (proteaphagy) in Arabidopsis can proceed via nonselective and selective routes, depending on the initial trigger.…”

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confidence: 99%