bims-apauto 2022-02-13 papers

Issue of 2022–02–13
six papers selected by
Su Hyun Lee, Seoul National University

Int J Biol Macromol. 2022 Feb 07. pii: S0141-8130(22)00236-7. [Epub ahead of print]

Beclin1-mediated interplay between autophagy and apoptosis: New understanding.

The definition for autophagy holds a 'single' meaning as a conserved cellular process that constitutes a recycling pathway for damaged organelles and long-lived proteins to maintain nutrient homeostasis and mediate quality control within the cell. But this process of autophagy may behave ambiguously depending on the physiological stress as the stress progresses in the cellular microenvironment; the 'single' meaning of the autophagy changes from the 'cytoplasmic turnover process' to 'tumor suppressive' and a farther extent, 'tumor promoter' process. In a tumorigenic state, the chemotherapy-mediated resistance and intolerance due to upregulated autophagy in cancer cells have become a significant concern. This concern has provided insight to the scientific community to enter into the arena of cross-talk between autophagy and apoptosis. Recent findings and ongoing research have provided insights on some of the key regulators of this cross-talk; one of them is Beclin1 and their involvement in the physiological and the pathophysiological processes; however, reconciliation of these two forms of death remains an arena to be explored extensively. This review sheds light on the interplay between autophagy and apoptosis, emphasizing one of the key players, Beclin1, and its importance in health and diseases.

Keywords: Apoptosis; Autophagy; Bcl-2; Beclin1; Tumor promoter; Tumor suppressor

DOI: https://doi.org/10.1016/j.ijbiomac.2022.02.005

Proc Natl Acad Sci U S A. 2022 Feb 15. pii: e2113454119. [Epub ahead of print]119(7):

TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation.

Di Liu, Zhiyao Zhao, Yuanchu She, Lei Zhang, Xiangtian Chen, Ling Ma, Jun Cui.

Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains unclear how autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as an epigenetic regulator that reduces histone H3K9 trimethylation by inhibiting the autophagic degradation of the histone demethylase KDM4D. TRIM14 recruited the deubiquitinases USP14 and BRCC3 to cleave the K63-linked ubiquitin chains of KDM4D, which prevented KDM4D from undergoing optineurin (OPTN)-mediated selective autophagy. Tripartite motif-containing 14 (TRIM14) deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines interleukin 12 (Il12) and Il23 and protected mice from autoimmune inflammation. Taken together, these findings highlight the cross-talk between epigenetic regulation and autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.

Keywords: KDM4D; TRIM14; autophagy; epigenetic regulation; inflammation

DOI: https://doi.org/10.1073/pnas.2113454119

Front Cell Dev Biol. 2022 ;10 817112

m6A: An Emerging Role in Programmed Cell Death.

Fajuan Tang, Lin Chen, Hu Gao, Dongqiong Xiao, Xihong Li.

Programmed cell death is an active extinction process, including autophagy, ferroptosis, pyroptosis, apoptosis, and necroptosis. m6A is a reversible RNA modification which undergoes methylation under the action of methylases (writers), and is demethylated under the action of demethylases (erasers). The RNA base site at which m6A is modified is recognized by specialized enzymes (readers) which regulate downstream RNA translation, decay, and stability. m6A affects many aspects of mRNA metabolism, and also plays an important role in promoting the maturation of miRNA, the translation and degradation of circRNA, and the stability of lncRNA. The regulatory factors including writers, erasers and readers promote or inhibit programmed cell death via up-regulating or down-regulating downstream targets in a m6A-dependent manner to participate in the process of disease. In this review, we summarize the functions of m6A with particular reference to its role in programmed cell death.

Keywords: apoptosis; autophagy; ferroptosis; m6A; necroptosis; pyroptosis

DOI: https://doi.org/10.3389/fcell.2022.817112

Clin Transl Oncol. 2022 Feb 08.

Autophagy deficiency promotes lung metastasis of prostate cancer via stabilization of TWIST1.

Y X Shi, Z W Sun, D L Jia, H B Wang.

PURPOSE: The role of autophagy in prostate cancer metastasis remains controversial, and the effects of the autophagy-related gene ATG5 on prostate cancer metastasis are poorly understood. This study aims to explore the effects of ATG5 on prostate cancer metastasis and its molecular mechanism.
METHODS: The metastatic characteristics of LNCaP and DU145 cells were assessed by NOD/SCID mouse experiments, western blot, transwell assay, and wound-healing assay. Double membrane autophagic vesicle observation and the adenovirus-expressing mCherry-GFP-LC3B fusion protein were used to assess the autophagic characteristics of LNCaP and DU145 cells. The role of p62 in the accumulation of TWIST1 was confirmed by western blot under different conditions. The lentivirus particles of shATG5, NOD/SCID mice experiments, western blot, transwell assay, and wound-healing assay were used to confirm the role of ATG5 in TWIST1 accumulation and prostate cancer cell metastasis.
RESULTS: We identified a stabilizing effect of p62 on TWIST1 in the autophagic regulation of EMT and prostate cancer metastasis. The loss of ATG5 in DU145 cells resulted in autophagy deficiency and p62 accumulation, which stabilized TWIST1 and increased the TWIST1 level in prostate cancer cells, and eventually promoted EMT and metastasis. In comparison, LNCaP cells with regular ATG5 expression and autophagy status retained remarkable epithelial cell characteristics and had limited metastatic characteristics. Similar results were also found in wild-type LNCaP cells and LNCaP cells with stable ATG5 interference.
CONCLUSIONS: Our research revealed ATG5-mediated autophagy as a key mechanism that controls the metastasis of prostate cancer by regulating p62 abundance and TWIST1 stabilization.

Keywords: ATG5; Metastasis; Phenotype crosstalk; TWIST1; p62 accumulation

DOI: https://doi.org/10.1007/s12094-022-02786-y

Cell Death Dis. 2022 Feb 10. 13(2): 139

Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation.

Rirong Chen, Xiaobai Pang, Li Li, Zhirong Zeng, Minhu Chen, Shenghong Zhang.

The exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn's disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-β; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.

DOI: https://doi.org/10.1038/s41419-022-04566-6

Autophagy. 2022 Feb 07. 1-18

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Bin Wang, Jing Zhang, Xin Liu, Qingqing Chai, Xiaoran Lu, Xiaoyu Yao, Zhichang Yang, Liangliang Sun, Silas F Johnson, Richard C Schwartz, Yong-Hui Zheng.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: β-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Keywords: Autophagy; ER-phagy; ERAD; ERp57; EVD; ebola; filoviruses; glycoproteins; lysosomes; reticulophagy

DOI: https://doi.org/10.1080/15548627.2022.2031381