bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023‒02‒26
eight papers selected by
Su Hyun Lee
Harvard University
  1. Editorial: Targeting autophagy in Cancer Therapy: Focus on small-molecule modulators and new strategies.
  2. Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling.
  3. E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
  4. The role of programmed mitophagy in germline mitochondrial DNA quality control.
  5. Structural basis for clearing of ribosome collisions by the RQT complex.
  6. A deep dive into degrader-induced protein-protein interfaces.
  7. Amino acid sensing and lysosomal signaling complexes.
  8. Mitochondrial DNA in cell death and inflammation.
  1. Front Pharmacol. 2023 ;14 1145255
    Editorial: Targeting autophagy in Cancer Therapy: Focus on small-molecule modulators and new strategies.
    Ryszard Pluta.
      
    Keywords:  autophagy; cancer; new strategies; small-molecule modulators; therapy
    DOI:  https://doi.org/10.3389/fphar.2023.1145255
  2. Nat Commun. 2023 Feb 22. 14(1): 978
    Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling.
    Fuchun Yang, Shiva Kalantari, Banzhan Ruan, Shaogang Sun, Zhaoqun Bian, Jun-Lin Guan.
      Lymphatic malformation (LM) is a vascular anomaly originating from lymphatic endothelial cells (ECs). While it mostly remains a benign disease, a fraction of LM patients progresses to malignant lymphangiosarcoma (LAS). However, very little is known about underlying mechanisms regulating LM malignant transformation to LAS. Here, we investigate the role of autophagy in LAS development by generating EC-specific conditional knockout of an essential autophagy gene Rb1cc1/FIP200 in Tsc1iΔEC mouse model for human LAS. We find that Fip200 deletion blocked LM progression to LAS without affecting LM development. We further show that inhibiting autophagy by genetical ablation of FIP200, Atg5 or Atg7, significantly inhibited LAS tumor cell proliferation in vitro and tumorigenicity in vivo. Transcriptional profiling of autophagy-deficient tumor cells and additional mechanistic analysis determine that autophagy plays a role in regulating Osteopontin expression and its down-stream Jak/Stat3 signaling in tumor cell proliferation and tumorigenicity. Lastly, we show that specifically disrupting FIP200 canonical autophagy function by knocking-in FIP200-4A mutant allele in Tsc1iΔEC mice blocked LM progression to LAS. These results demonstrate a role for autophagy in LAS development, suggesting new strategies for preventing and treating LAS.
    DOI:  https://doi.org/10.1038/s41467-023-36562-5
  3. Mol Cell. 2023 Feb 10. pii: S1097-2765(23)00042-4. [Epub ahead of print]
    E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
    Daniel C Scott, Moeko T King, Kheewoong Baek, Clifford T Gee, Ravi Kalathur, Jerry Li, Nicholas Purser, Amanda Nourse, Sergio C Chai, Sivaraja Vaithiyalingam, Taosheng Chen, Richard E Lee, Stephen J Elledge, Gary Kleiger, Brenda A Schulman.
      E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins with terminal degron-like sequences remains unclear. Here, we report that human KLHDC2, a CRL2 substrate receptor targeting C-terminal Gly-Gly degrons, is regulated through interconversion between two assemblies. In the self-inactivated homotetramer, KLHDC2's C-terminal Gly-Ser motif mimics a degron and engages the substrate-binding domain of another protomer. True substrates capture the monomeric CRL2KLHDC2, driving E3 activation by neddylation and subsequent substrate ubiquitylation. Non-substrates such as NEDD8 bind KLHDC2 with high affinity, but its slow on rate prevents productive association with CRL2KLHDC2. Without substrate, neddylated CRL2KLHDC2 assemblies are deactivated via distinct mechanisms: the monomer by deneddylation and the tetramer by auto-ubiquitylation. Thus, substrate specificity is amplified by KLHDC2 self-assembly acting like a molecular timer, where only bona fide substrates may bind before E3 ligase inactivation.
    Keywords:  Autoinhibition; C-END degron; CUL2; Cullin-RING Ligase; E3; KLHDC10; KLHDC3; Kinetic proofreading; NEDD8; Targeted protein degradation; allostery; higher-order assembly; protein-protein interaction; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.01.019
  4. Autophagy. 2023 Feb 20.
    The role of programmed mitophagy in germline mitochondrial DNA quality control.
    Jonathan M Palozzi, Thomas R Hurd.
      Mitochondrial DNA (mtDNA) is prone to the accumulation of mutations. To prevent harmful mtDNA mutations from being passed on to the next generation, the female germline, through which mtDNA is exclusively inherited, has evolved extensive mtDNA quality control. To dissect the molecular underpinnings of this process, we recently performed a large RNAi screen in Drosophila and uncovered a programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We found that PGM begins as germ cells enter meiosis, induced, at least in part, by the inhibition of the mTor (mechanistic Target of rapamycin) complex 1 (mTorC1). Interestingly, PGM requires the general macroautophagy/autophagy machinery and the mitophagy adaptor BNIP3, but not the canonical mitophagy genes Pink1 and park (parkin), even though they are critical for germline mtDNA quality control. We also identified the RNA-binding protein Atx2 as a major regulator of PGM. This work is the first to identify and implicate a programmed mitophagy event in germline mtDNA quality control, and it highlights the utility of the Drosophila ovary for studying developmentally regulated mitophagy and autophagy in vivo.
    Keywords:  Drosophila; autophagy; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection
    DOI:  https://doi.org/10.1080/15548627.2023.2182595
  5. Nat Commun. 2023 Feb 17. 14(1): 921
    Structural basis for clearing of ribosome collisions by the RQT complex.
    Katharina Best, Ken Ikeuchi, Lukas Kater, Daniel Best, Joanna Musial, Yoshitaka Matsuo, Otto Berninghausen, Thomas Becker, Toshifumi Inada, Roland Beckmann.
      Translation of aberrant messenger RNAs can cause stalling of ribosomes resulting in ribosomal collisions. Collided ribosomes are specifically recognized to initiate stress responses and quality control pathways. Ribosome-associated quality control facilitates the degradation of incomplete translation products and requires dissociation of the stalled ribosomes. A central event is therefore the splitting of collided ribosomes by the ribosome quality control trigger complex, RQT, by an unknown mechanism. Here we show that RQT requires accessible mRNA and the presence of a neighboring ribosome. Cryogenic electron microscopy of RQT-ribosome complexes reveals that RQT engages the 40S subunit of the lead ribosome and can switch between two conformations. We propose that the Ski2-like helicase 1 (Slh1) subunit of RQT applies a pulling force on the mRNA, causing destabilizing conformational changes of the small ribosomal subunit, ultimately resulting in subunit dissociation. Our findings provide conceptual framework for a helicase-driven ribosomal splitting mechanism.
    DOI:  https://doi.org/10.1038/s41467-023-36230-8
  6. Trends Pharmacol Sci. 2023 Feb 22. pii: S0165-6147(23)00035-4. [Epub ahead of print]
    A deep dive into degrader-induced protein-protein interfaces.
    Pius Galli, Carlos Pla-Prats, Nicolas H Thomä.
      Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al. introduced deep mutational scanning (DMS) in combination with structural and biochemical approaches to identify residues crucial for degrader activity.
    Keywords:  degrader resistance; saturation mutagenesis; targeted protein degradation; ubiquitin ligase
    DOI:  https://doi.org/10.1016/j.tips.2023.02.001
  7. Curr Opin Struct Biol. 2023 Feb 16. pii: S0959-440X(23)00018-0. [Epub ahead of print]79 102544
    Amino acid sensing and lysosomal signaling complexes.
    Zhicheng Cui, Aaron M N Joiner, Rachel M Jansen, James H Hurley.
      Amino acid pools in the cell are monitored by dedicated sensors, whose structures are now coming into view. The lysosomal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in detail. For FLCN-FNIP, the entire chain of events from the arginine transporter SLC38A9 to substrate-specific mTORC1 activation has been visualized. The structure GATOR2 has been determined, hinting at an ordering of amino acid signaling across a larger size scale than anticipated. The centerpiece of lysosomal signaling, mTORC1, has been revealed to recognize its substrates by more nuanced and substrate-specific mechanisms than previous appreciated. Beyond the well-studied Rag GTPase and mTORC1 machinery, another lysosomal amino acid sensor/effector system, that of PQLC2 and the C9orf72-containing CSW complex, is coming into structural view. These developments hold promise for further insights into lysosomal physiology and lysosome-centric therapeutics.
    DOI:  https://doi.org/10.1016/j.sbi.2023.102544
  8. Biochem Soc Trans. 2023 Feb 23. pii: BST20221525. [Epub ahead of print]
    Mitochondrial DNA in cell death and inflammation.
    Rosalie Heilig, Jordan Lee, Stephen W G Tait.
      Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.
    Keywords:  apoptosis; cell death; mitochondria; mtDNA; pyroptosis
    DOI:  https://doi.org/10.1042/BST20221525
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