bims-apauto 2022-05-22 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2022–05–22
seven papers selected by
Su Hyun Lee, Seoul National University

N7-methylguanosine (m7G) tRNA modification: a novel autophagy modulator in cancer.
Autophagy regulation by RNA alternative splicing and implications in human diseases.
Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates.
A CRISPR view on autophagy.
SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
Targeting the apoptosis pathway to treat tumours of the paediatric nervous system.
Autophagy Inhibition Enhances the Anti-Tumor Activity of Methylseleninic Acid in Cisplatin-Resistance Human Lung Adenocarcinoma Cells.

Autophagy. 2022 May 16.

N7-methylguanosine (m7G) tRNA modification: a novel autophagy modulator in cancer.

Hui Han, Siyi Zheng, Shuibin Lin.

  Macroautophagy/autophagy, a physiological process that is involved in tumorigenesis, is regulated at genetic and epigenetic levels. Emerging reports suggest that aberrant RNA modifications cause dysregulated autophagy and affect tumorigenesis, while the role of RNA modifications in the regulation of autophagy in cancers remains unclear. In a recent study, we describe a new role for the tRNA m7G methyltransferase complex components METTL1 and WDR4 as negative regulators of MTORC1-mediated autophagy in esophageal squamous cell carcinoma (ESCC). METTL1 and WDR4 show abnormally high expression in ESCC tissues, and are associated with poor ESCC prognosis. Targeting METTL1 or WDR4 leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts, including the genes related to the MTOR signaling pathway and negative regulators of autophagy in an m7G-related codon-dependent manner, thereby resulting in hyperactivated MTORC1-mediated autophagy via dephosphorylation of ULK1 and finally causes cell death in ESCC. Our findings provide a new layer of translation regulation mechanism mediated by tRNA m7G modification, link translational machinery with autophagic machinery, and suggest that METTL1 and its downstream signaling axis could be potential therapeutic targets for ESCC treatment.

Keywords:  Autophagy; METTL1; esophageal squamous cell carcinoma; m7G; tRNA modification

DOI:  https://doi.org/10.1080/15548627.2022.2077551
Nat Commun. 2022 May 18. 13(1): 2735

Autophagy regulation by RNA alternative splicing and implications in human diseases.

Patricia González-Rodríguez, Daniel J Klionsky, Bertrand Joseph.

Autophagy and RNA alternative splicing are two evolutionarily conserved processes involved in overlapping physiological and pathological processes. However, the extent of functional connection is not well defined. Here, we consider the role for alternative splicing and generation of autophagy-related gene isoforms in the regulation of autophagy in recent work. The impact of changes to the RNA alternative splicing machinery and production of alternative spliced isoforms on autophagy are reviewed with particular focus on disease relevance. The use of drugs targeting both alternative splicing and autophagy as well as the selective regulation of single autophagy-related protein isoforms, are considered as therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-022-30433-1
Nat Commun. 2022 May 18. 13(1): 2736

Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates.

Fredrik Trulsson, Vyacheslav Akimov, Mihaela Robu, Nila van Overbeek, David Aureliano Pérez Berrocal, Rashmi G Shah, Jürgen Cox, Girish M Shah, Blagoy Blagoev, Alfred C O Vertegaal.

The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely unknown. Here, we compare the contributions of the proteasome and DUBs on the global ubiquitinome, using UbiSite technology, inhibitors and mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates and sites preferentially regulated by DUBs or by the proteasome, highlighting the role of DUBs in degradation-independent ubiquitination. DUBs regulate substrates via at least 40,000 unique sites. Regulated networks of ubiquitin substrates are involved in autophagy, apoptosis, genome integrity, telomere integrity, cell cycle progression, mitochondrial function, vesicle transport, signal transduction, transcription, pre-mRNA splicing and many other cellular processes. Moreover, we show that ubiquitin conjugated to SUMO2/3 forms a strong proteasomal degradation signal. Interestingly, PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity. Our study uncovers key regulatory roles of DUBs and provides a resource of endogenous ubiquitination sites to aid the analysis of substrate specific ubiquitin signalling.

DOI: https://doi.org/10.1038/s41467-022-30376-7
Trends Cell Biol. 2022 May 14. pii: S0962-8924(22)00107-6. [Epub ahead of print]

A CRISPR view on autophagy.

Jin Rui Liang, Jacob E Corn.

  Autophagy is a fundamental pathway for the degradation of cytoplasmic content in response to pleiotropic extracellular and intracellular stimuli. Recent advances in the autophagy field have demonstrated that different organelles can also be specifically targeted for autophagy with broad implications on cellular and organismal health. This opens new dimensions in the autophagy field and more unanswered questions on the rationale and underlying mechanisms to degrade different organelles. Functional genomics via clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based screening has gained popularity in the autophagy field to understand the common and unique factors that are implicated in the signaling, recognition, and execution of different cargo-specific autophagies. We focus on recent applications of CRISPR-based screens in the autophagy field, their discoveries, and the future directions of autophagy screens.

Keywords:  CRISPR; autophagy; functional genomics; genome-wide screens; organellophagy

DOI:  https://doi.org/10.1016/j.tcb.2022.04.006
Autophagy. 2022 May 19. 1-2

SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.

Xiao-Yan Fan, Shen Yin, Shi-Ming Luo.

  Mitophagy is a process that selectively degrades mitochondria in cells, and it involves a series of signaling events. Our recent paper shows that the ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (Binding) at the mitochondrial outer membrane, can directly cause mitophagy. To distinguish this mitophagy from others, we called it forced mitophagy. Further results show that the forced mitophagy can degrade half of the mitochondria and their DNA in HeLa cells and mouse embryos. Meanwhile, there are no apparent effects on mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitosis and embryo development. Thus, the forced mitophagy was examined to selectively degrade mitochondrial carryover in the nuclear donor embryos' mitochondria by pre-labeling with Binding before mitochondrial replacement therapy (MRT). The results show that the forced mitophagy can reduce mitochondrial carryover from an average of 4% to 0.09% compared to the controls in mouse embryos and tissues. In addition, the offspring from MRT mice show negligible effects on growth, reproduction, exercise and behavior. Furthermore, results from human tri-pronuclear embryos show that the forced mitophagy results in undetectable mitochondrial carryover in 77% of embryos following MRT. Therefore, forced mitophagy is efficient and safe for degrading mitochondrial carryover in MRT.

Keywords:  Forced mitophagy; NIX; SQSTM1; mitochondrial carryover; mitochondrial replacement therapy

DOI:  https://doi.org/10.1080/15548627.2022.2077552
Cell Death Dis. 2022 May 14. 13(5): 460

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system.

Marie-Claire Fitzgerald, Philip J O'Halloran, Niamh M C Connolly, Brona M Murphy.

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings.

DOI: https://doi.org/10.1038/s41419-022-04900-y
Front Pharmacol. 2022 ;13 890974

Autophagy Inhibition Enhances the Anti-Tumor Activity of Methylseleninic Acid in Cisplatin-Resistance Human Lung Adenocarcinoma Cells.

Ming Xin, Qi Gao, Xindong Xiang, Juanjuan Xu, Yuhan Jiao, Xuan Li, Xianzhen Zhang, Xiuqin Jia.

  Cisplatin (DDP)-based chemotherapy remains one of the standard treatment options for patients with advanced lung adenocarcinoma (LUAD), and cisplatin resistance is the biggest challenge to this therapy. Autophagy is also closely associated with chemoresistance in LUAD. Desperately need to find a way to improve the treatment efficiency of cisplatin-resistant LUAD in clinical practice. Previous studies reported that methylseleninic acid (MSA) has good anti-proliferation and pro-apoptotic activities in tumor cells. However, the effectiveness of MSA on cisplatin-resistant LUAD and its effect on the induction of autophagy is still unclear. In the current study, we found that MSA effectively inhibited the proliferation of LUAD cell lines and triggered mitochondrial pathway-mediated apoptosis. This effect was more pronounced in cisplatin-resistant LUAD cells with high MDR1 expression. In contrast, the mitochondrial damage caused by MSA treatment can be degraded by inducing selective autophagy in LUAD cells, thereby exerting a self-protective effect on tumor cells. Mechanistically, MSA inhibits proliferation, promotes apoptosis, and induces autophagy in LUAD cells by inhibiting of the Akt/mTOR pathway. Combination with autophagy inhibitors reduces the effect of this selective autophagy-induced resistance, and thus enhancing even more the anti-tumor effect of MSA on cisplatin-resistant LUAD cells. Finally, We speculate that MSA in combination with autophagy inhibitors may be a promising new therapeutic strategy for the treatment of cisplatin-resistant LUAD.

Keywords:  Akt/mTOR; MSA; apoptosis; autophagy; cisplatin-resistance; lung adenocarcinoma

DOI:  https://doi.org/10.3389/fphar.2022.890974