bims-apauto 2021-08-22 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2021–08–22
ten papers selected by
Su Hyun Lee, Seoul National University

Autophagy is a major metabolic regulator involved in cancer therapy resistance.
Selective Autophagy.
TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.
Torin 1 alleviates impairment of TFEB-mediated lysosomal biogenesis and autophagy in TGFBI (p.G623_H626del)-linked Thiel-Behnke corneal dystrophy.
DAXX represents a new type of protein-folding enabler.
UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1.
Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response.
Autophagy impairment by African swine fever virus.
Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD.
Advances in deubiquitinating enzymes in lung adenocarcinoma.

Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00959-1. [Epub ahead of print]36(7): 109528

Autophagy is a major metabolic regulator involved in cancer therapy resistance.

Laura Poillet-Perez, Jean-Emmanuel Sarry, Carine Joffre.

  Autophagy sustains cellular homeostasis and metabolism in numerous diseases. By regulating cancer metabolism, both tumor and microenvironmental autophagy promote tumor growth. However, autophagy can support cancer progression through other biological functions such as immune response regulation or cytokine/growth factor secretion. Moreover, autophagy is induced in numerous tumor types as a resistance mechanism following therapy, highlighting autophagy inhibition as a promising target for anti-cancer therapy. Thus, better understanding the mechanisms involved in tumor growth and resistance regulation through autophagy, which are not fully understood, will provide insights into patient treatment.

Keywords:  Poillet-Perez et al. review how both tumor and microenvironmental autophagy promote tumor growth by regulating cancer metabolism and the immune response. Moreover; autophagy is induced as a cell death or resistance mechanism following therapy. Better understanding the role of autophagy and the mechanisms involved will provide insights into patient treatment

DOI:  https://doi.org/10.1016/j.celrep.2021.109528
Cancer Sci. 2021 Aug 18.

Selective Autophagy.

Mohammad Omar Faruk, Yoshinobu Ichimura, Masaaki Komatsu.

  While starvation-induced autophagy is thought to randomly degrade cellular components, under certain circumstances autophagy selectively recognizes, sequesters, and degrades specific targets via autophagosomes. This process is called selective autophagy, and it contributes to cellular homeostasis by degrading specific soluble proteins, supramolecular complexes, liquid-liquid phase-separated droplets, abnormal or excess organelles, and pathogenic invasive bacteria. This means that autophagy, like the ubiquitin-proteasome system, strictly regulates diverse cellular functions through its selectivity. In this short review, we focus on the mechanism of "selective" autophagy, which is rapidly being elucidated.

Keywords:  ; autophagy; ATG8-family proteins; liquid-liquid phase separation; selective autophagy; selective autophagy receptors

DOI:  https://doi.org/10.1111/cas.15112
Acta Pharmacol Sin. 2021 Aug 20.

TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.

Chuan-Bin Yang, Jia Liu, Benjamin Chun-Kit Tong, Zi-Ying Wang, Zhou Zhu, Cheng-Fu Su, Sravan Gopalkrishnashetty Sreenivasmurthy, Jia-Xi Wu, Ashok Iyaswamy, Senthilkumar Krishnamoorthi, Shi-Ying Huang, King-Ho Cheung, Ju-Xian Song, Jie-Qiong Tan, Jia-Hong Lu, Min Li.

  Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.

Keywords:  15-deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2); ATF4; ER stress; apoptosis; autophagy and lysosome biogenesis; transcriptional factor EB (TFEB)

DOI:  https://doi.org/10.1038/s41401-021-00711-7
Autophagy. 2021 Aug 17. 1-18

Torin 1 alleviates impairment of TFEB-mediated lysosomal biogenesis and autophagy in TGFBI (p.G623_H626del)-linked Thiel-Behnke corneal dystrophy.

Liyuan Wang, Chuchu Zhao, Tao Zheng, Yi Zhang, Hanruo Liu, Xi Wang, Xianling Tang, Baowen Zhao, Ping Liu.

  Thiel-Behnke corneal dystrophy (TBCD) is an epithelial-stromal TGFBI dystrophy caused by mutations in the TGFBI (transforming growth factor beta induced) gene, though the underlying mechanisms and pathogenesis of TBCD are still obscure. The study identifies a novel mutation in the TGFBI gene (p.Gly623_His626del) in a TBCD pedigree. Characteristics of the typical vacuole formation, irregular corneal epithelial thickening and thinning, deposition of eosinophilic substances beneath the epithelium, and involvement of the anterior stroma were observed in this pedigree via transmission electron microscopy (TEM) and histological staining. Tgfbi-p.Gly623_Tyr626del mouse models of TBCD were subsequently generated via CRISPR/Cas9 technology, and the above characteristics were further verified via TEM and histological staining. Lysosomal dysfunction and downregulation of differential expression protein CTSD (cathepsin D) were observed using LysoTracker Green DND-26 and proteomic analysis, respectively. Hence, lysosomal dysfunction probably leads to autophagic flux obstruction in TBCD; this was supported by enhanced LC3-II and SQSTM1 levels and decreased CTSD. TFEB (transcription factor EB) was prominently decreased in TBCD corneal fibroblasts and administration of ATP-competitive MTOR inhibitor torin 1 reversed this decline, resulting in the degradation of accumulated mut-TGFBI (mutant TGFBI protein) via the ameliorative lysosomal function and autophagic flux owing to elevated TFEB activity as measured by western blot, confocal microscopy, and flow cytometry. Transfected HEK 293 cells overexpressing human full-length WT-TGFBI and mut-TGFBI were generated to further verify the results obtained in human corneal fibroblasts. Amelioration of lysosome dysfunction may therefore have therapeutic efficacy in the treatment of TBCD.

Keywords:  Autophagy; TBCD; TFEB; TGFBI; lysosome dysfunction; torin 1

DOI:  https://doi.org/10.1080/15548627.2021.1955469
Nature. 2021 Aug 18.

DAXX represents a new type of protein-folding enabler.

Liangqian Huang, Trisha Agrawal, Guixin Zhu, Sixiang Yu, Liming Tao, JiaBei Lin, Ronen Marmorstein, James Shorter, Xiaolu Yang.

Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3-10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism.

DOI: https://doi.org/10.1038/s41586-021-03824-5
Cell Signal. 2021 Aug 12. pii: S0898-6568(21)00207-2. [Epub ahead of print] 110118

UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1.

Xun Wang, Ping Yang, Yongliang Jiang, Yazhou Xu, Nan Wang, Peng Rao, Lin Yang, Lin Sun, Di Lu.

  The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome(UPS) participate in the multitudinous progression of disease by interactive relationship. Especially UBE2D3, the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiquitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1.

Keywords:  Autophagy; Myocardial ischemia-reperfusion injury; UBE2D3; Ubiquitylation; p62/SQSTM1

DOI:  https://doi.org/10.1016/j.cellsig.2021.110118
J Biol Chem. 2021 Aug 12. pii: S0021-9258(21)00880-2. [Epub ahead of print] 101077

Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response.

Nathan A Snyder, Gustavo M Silva.

  Ubiquitin signaling is a conserved, widespread, and dynamic system in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization or stability. To regulate this system, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein-protein interaction, post-translational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.

Keywords:  DUB; deubiquitination; enzymatic regulation; oxidative stress; redox signaling; translation; ubiquitin

DOI:  https://doi.org/10.1016/j.jbc.2021.101077
J Gen Virol. 2021 Aug;102(8):

Autophagy impairment by African swine fever virus.

Gareth L Shimmon, Joshua Y K Hui, Thomas E Wileman, Christopher L Netherton.

  African swine fever is a devastating disease of domestic swine and wild boar caused by a large double-stranded DNA virus that encodes for more than 150 open reading frames. There is no licensed vaccine for the disease and the most promising current candidates are modified live viruses that have been attenuated by deletion of virulence factors. Like many viruses African swine fever virus significantly alters the host cell machinery to benefit its replication and viral genes that modify host pathways represent promising targets for development of gene deleted vaccines. Autophagy is an important cellular pathway that is involved in cellular homeostasis, innate and adaptive immunity and therefore is manipulated by a number of different viruses. Autophagy is regulated by a complex protein cascade and here we show that African swine fever virus can block formation of autophagosomes, a critical functional step of the autophagy pathway through at least two different mechanisms. Interestingly this does not require the A179L gene that has been shown to interact with Beclin-1, an important autophagy regulator.

Keywords:  African swine fever; DNA virus; host-pathogen interactions; immune evasion; transcription

DOI:  https://doi.org/10.1099/jgv.0.001637
Nat Commun. 2021 08 18. 12(1): 5004

Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD.

Luke A Perera, Steffen Preissler, Nathan R Zaccai, Sylvain Prévost, Juliette M Devos, Michael Haertlein, David Ron.

The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both BiP AMPylation and deAMPylation are catalysed by a single ER-localised enzyme, FICD. Here we present crystallographic and solution structures of a deAMPylation Michaelis complex formed between mammalian AMPylated BiP and FICD. The latter, via its tetratricopeptide repeat domain, binds a surface that is specific to ATP-state Hsp70 chaperones, explaining the exquisite selectivity of FICD for BiP's ATP-bound conformation both when AMPylating and deAMPylating Thr518. The eukaryotic deAMPylation mechanism thus revealed, rationalises the role of the conserved Fic domain Glu234 as a gatekeeper residue that both inhibits AMPylation and facilitates hydrolytic deAMPylation catalysed by dimeric FICD. These findings point to a monomerisation-induced increase in Glu234 flexibility as the basis of an oligomeric state-dependent switch between FICD's antagonistic activities, despite a similar mode of engagement of its two substrates - unmodified and AMPylated BiP.

DOI: https://doi.org/10.1038/s41467-021-25076-7
J Cancer. 2021 ;12(18): 5573-5582

Advances in deubiquitinating enzymes in lung adenocarcinoma.

Xi-Jia Zhou, Rui Li, Xiao Liu, Yi-Qing Qu.

  The process of ubiquitination and deubiquitination is widely present in the human body's protein reactions and plays versatile roles in multiple diseases. Deubiquitinating enzymes (DUBs) are significant regulators of this process, which cleave the ubiquitin (Ub) moiety from various substrates and maintain protein stability. Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer (NSCLC) and remains refractory to treatment. To elucidate the mechanism of LUAD and advance new therapeutic targets, we review the latest research progress on DUBs in LUAD. We summarize the biological capabilities of these DUBs and further highlight those DUBs that may serve as anticancer target candidates for precision treatment. We also discuss deubiquitinase inhibitors, which are expected to play a role in targeted LUAD therapy.

Keywords:  deubiquitinase inhibitor; deubiquitinating enzymes; lung adenocarcinoma; targeted therapy

DOI:  https://doi.org/10.7150/jca.56532