bims-apauto 2022-04-03 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2022–04–03
eight papers selected by
Su Hyun Lee, Seoul National University

Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.
Transmembrane protein ATG-9 links presynaptic autophagy with the synaptic vesicle cycle.
Upstream open reading frames mediate autophagy-related protein translation.
Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
The mitophagosome, a novel ultrastructure of mitophagy in the alcoholic steatohepatitis mouse model: a transmission electron microscope study.
Usp8 promotes tumor cell migration through activating the JNK pathway.
Alternative autophagy: mechanisms and roles in different diseases.
The Ubiquitin Ligase RNF34 Participates in the Peripheral Quality Control of CFTR (RNF34 Role in CFTR PeriQC).

Mol Cell. 2022 Mar 29. pii: S1097-2765(22)00221-0. [Epub ahead of print]

Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.

Ellen A Goodall, Felix Kraus, J Wade Harper.

  Selective autophagy specifically eliminates damaged or superfluous organelles, maintaining cellular health. In this process, a double membrane structure termed an autophagosome captures target organelles or proteins and delivers this cargo to the lysosome for degradation. The attachment of the small protein ubiquitin to cargo has emerged as a common mechanism for initiating organelle or protein capture by the autophagy machinery. In this process, a suite of ubiquitin-binding cargo receptors function to initiate autophagosome assembly in situ on the target cargo, thereby providing selectivity in cargo capture. Here, we review recent efforts to understand the biochemical mechanisms and principles by which cargo are marked with ubiquitin and how ubiquitin-binding cargo receptors use conserved structural modules to recruit the autophagosome initiation machinery, with a particular focus on mitochondria and intracellular bacteria as cargo. These emerging mechanisms provide answers to long-standing questions in the field concerning how selectivity in cargo degradation is achieved.

Keywords:  cargo receptor; mitophagy; selective autophagy; ubiquitin; xenophagy

DOI:  https://doi.org/10.1016/j.molcel.2022.03.012
Autophagy. 2022 Mar 29. 1-2

Transmembrane protein ATG-9 links presynaptic autophagy with the synaptic vesicle cycle.

Sisi Yang, Daniel A Colón-Ramos.

  Macroautophagy/autophagy occurs preferentially at synapses and responds to increased neuronal activity states. How synaptic autophagy is coupled to the neuronal activity state is largely unknown. Through genetic approaches we find that ATG-9, the only transmembrane protein in the core autophagy pathway, is transported from the trans-Golgi network to synapses in C. elegans via the AP-3 complex. At synapses ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt the endocytosis pathway, including a mutation associated with early onset Parkinsonism (EOP), lead to abnormal ATG-9 accumulation into subsynaptic clathrin-rich foci, and defects in activity-induced synaptic autophagy. We propose that ATG-9 exo-endocytosis links the activity-dependent synaptic vesicle cycle with autophagosome formation at synapses.

Keywords:  AP-3; ATG-9; Golgi apparatus; Parkinson disease; autophagy; clathrin; endocytosis; neuronal activity state; synaptic vesicle cycle; synaptojanin 1/UNC-26

DOI:  https://doi.org/10.1080/15548627.2022.2049151
Autophagy. 2022 Apr 01.

Upstream open reading frames mediate autophagy-related protein translation.

Ying Yang, Damian Gatica Mizala, Xu Liu, Runliu Wu, Rui Kang, Daolin Tang, Daniel J Klionsky.

  Macroautophagy/autophagy, a highly conserved catabolic pathway that maintains proper cellular homeostasis is stringently regulated by numerous autophagy-related (Atg) proteins. Many studies have investigated autophagy regulation at the transcriptional level; however, relatively little is known about translational control. Here, we report the upstream open reading frames (uORFs)-mediated translational control of multiple Atg proteins in Saccharomyces cerevisiae and in human cells. The translation of several essential autophagy regulators in yeast, including Atg13, is suppressed by canonical uORFs under nutrient-rich conditions, and is activated during nitrogen-starvation conditions. We also found that the predicted human ATG4B and ATG12 non-canonical uORFs suppress downstream coding sequence translation. These results demonstrate that uORF-mediated translational control is a widely used mechanism among ATG genes from yeast to human and suggest a model for how some ATG genes bypass the general translational suppression that occurs under stress conditions to maintain a proper level of autophagy.

Keywords:  Autophagy; human; lysosome; stress; translational regulation; vacuole; yeast

DOI:  https://doi.org/10.1080/15548627.2022.2059744
Autophagy. 2022 Mar 29. 1-3

Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.

Juliet Goldsmith, Erika L F Holzbaur.

  Neurons depend on macroautophagy/autophagy to maintain cellular homeostasis, and loss of autophagy leads to neurodegeneration. To better understand the role of basal autophagy in neurons, we enriched autophagic vesicles from healthy adult mouse brain and performed mass spectrometry to identify cargos cleared by autophagy. We found that synaptic and mitochondrial proteins comprise nearly half of the unique AV cargos identified in brain. Similarly, synaptic and mitochondrial proteins are major cargos for basal autophagy in neurons. Strikingly, we noted a specific enrichment of mitochondrial nucleoids within neuronal autophagosomes, which occurs through a mechanism distinct from damage-associated mitophagy. Here, we discuss the implications of these findings for our understanding of homeostatic mechanisms in neurons and how the age-dependent decline of autophagy in neurons may contribute to the onset or progression of neurodegenerative disease.

Keywords:  DNM1L; SYN1; TFAM; macroautophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1080/15548627.2022.2056865
Ultrastruct Pathol. 2022 Mar 29. 1-8

The mitophagosome, a novel ultrastructure of mitophagy in the alcoholic steatohepatitis mouse model: a transmission electron microscope study.

Yanfei Lang, Xiaxia Zhang, Xin Li, Youqing Xu.

  Acute alcohol feeding can activate autophagy and promotes the selection of autophagic vacuoles in the mitochondria, which is a key process regulating the occurrence and progression of alcohol steatohepatitis (ASH). In this study, ASH mice expressed more autophagy-associated proteins than healthy controls, as revealed by immunohistochemistry. In addition, transmission electron microscopy (TEM) detected a unique autophagy ultrastructure in ASH mouse liver cells, consisting of a large vesicle fused directly with mitochondria, which differed from the classical pattern. This novel type of mitophagy may provide a new avenue for a protective mechanism targeting mitophagy, which would benefit patients with ASH.Abbreviations: ASH: alcoholic steatohepatitis; ALD: Alcoholic liver disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; HE: hematoxylin and eosin; TEM: transmission electron microscope; LC3: microtubule-associated protein 1 light chain 3; SQSTM1/p62: sequestosome 1; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; PINK1: PTEN induced kinase 1; AMPK: AMP-activated protein kinase.

Keywords:  Alcoholic steatohepatitis; mitophagy; selective autophagy; transmission electron microscope

DOI:  https://doi.org/10.1080/01913123.2022.2059041
Cell Death Dis. 2022 Mar 31. 13(3): 286

Usp8 promotes tumor cell migration through activating the JNK pathway.

Yunhe Zhao, Dezhen Peng, Yanyun Liu, Qian Zhang, Bin Liu, Yanran Deng, Wenhao Ding, Zizhang Zhou, Qingxin Liu.

Tumor metastasis is the most cause of high mortality for cancer patients. Identification of novel factors that modulate tumor cell migration is of great significance for therapeutic strategies. Here, we find that the ubiquitin-specific protease 8 (Usp8) promotes tumor cell migration through activating the c-Jun N-terminal kinase (JNK) pathway. Genetic epistasis analyses uncover Usp8 acts upstream of Tak1 to control the JNK pathway. Consistently, biochemical results reveal that Usp8 binds Tak1 to remove ubiquitin modification from Tak1, leading to its stabilization. In addition, human USP8 also triggers tumor cell migration and activates the JNK pathway. Finally, we show that knockdown of USP8 in human breast cancer cells suppresses cell migration. Taken together, our findings demonstrate that a conserved Usp8-Tak1-JNK axis promotes tumor cell migration, and providing USP8 as a potential therapeutic target for cancer treatment.

DOI: https://doi.org/10.1038/s41419-022-04749-1
Cell Commun Signal. 2022 Mar 31. 20(1): 43

Alternative autophagy: mechanisms and roles in different diseases.

Hong Feng, Nian Wang, Nan Zhang, Hai-Han Liao.

  As an important mechanism to maintain cellular homeostasis, autophagy exerts critical functions via degrading misfolded proteins and damaged organelles. Recent years, alternative autophagy, a new type of autophagy has been revealed, which shares similar morphology with canonical autophagy but is independent of Atg5/Atg7. Investigations on different diseases showed the pivotal role of alternative autophagy during their physio-pathological processes, including heart diseases, neurodegenerative diseases, oncogenesis, inflammatory bowel disease (IBD), and bacterial infection. However, the studies are limited and the precise roles and mechanisms of alternative autophagy are far from clear. It is necessary to review current research on alternative autophagy and get some hint in order to provide new insight for further study. Video Abstract.

Keywords:  Alternative autophagy; Canonical autophagy; Diseases; Mechanism; Non-canonical autophagy

DOI:  https://doi.org/10.1186/s12964-022-00851-1
Front Mol Biosci. 2022 ;9 840649

The Ubiquitin Ligase RNF34 Participates in the Peripheral Quality Control of CFTR (RNF34 Role in CFTR PeriQC).

Shogo Taniguchi, Yukiko Ito, Hibiki Kiritani, Asuka Maruo, Ryohei Sakai, Yuji Ono, Ryosuke Fukuda, Tsukasa Okiyoneda.

  The peripheral protein quality control (periQC) system eliminates the conformationally defective cystic fibrosis transmembrane conductance regulator (CFTR), including ∆F508-CFTR, from the plasma membrane (PM) and limits the efficacy of pharmacological therapy for cystic fibrosis (CF). The ubiquitin (Ub) ligase RFFL is responsible for the chaperone-independent ubiquitination and lysosomal degradation of CFTR in the periQC. Here, we report that the Ub ligase RNF34 participates in the CFTR periQC in parallel to RFFL. An in vitro study reveals that RNF34 directly recognizes the CFTR NBD1 and selectively promotes the ubiquitination of unfolded proteins. RNF34 was localized in the cytoplasm and endosomes, where RFFL was equally colocalized. RNF34 ablation increased the PM density as well as the mature form of ∆F508-CFTR rescued at low temperatures. RFFL ablation, with the exception of RNF34 ablation, increased the functional PM expression of ∆F508-CFTR upon a triple combination of CFTR modulators (Trikafta) treatment by inhibiting the K63-linked polyubiquitination. Interestingly, simultaneous ablation of RNF34 and RFFL dramatically increased the functional PM ∆F508-CFTR by inhibiting the ubiquitination in the post-Golgi compartments. The CFTR-NLuc assay demonstrates that simultaneous ablation of RNF34 and RFFL dramatically inhibits the degradation of mature ∆F508-CFTR after Trikafta treatment. Therefore, these results suggest that RNF34 plays a crucial role in the CFTR periQC, especially when there is insufficient RFFL. We propose that simultaneous inhibition of RFFL and RNF34 may improve the efficacy of CFTR modulators.

Keywords:  CFTR; RFFL; RNF34; Trikafta; cystic fibrosis; peripheral quality control; ubiquitin ligase

DOI:  https://doi.org/10.3389/fmolb.2022.840649