bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2022‒09‒25
eight papers selected by
Su Hyun Lee
Seoul National University
  1. Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway.
  2. Autophagy is a novel pathway for neurofilament protein degradation in vivo.
  3. Non-invasive monitoring of autophagy.
  4. Targeting of biomolecular condensates to the autophagy pathway.
  5. Targeted Protein Degradation via Lysosomes.
  6. Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?
  7. Protein condensation diseases: therapeutic opportunities.
  8. Editorial: Stress response signaling in tumor development and its implications for cancer treatment.
  1. Biomedicines. 2022 Aug 27. pii: 2100. [Epub ahead of print]10(9):
    Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway.
    Hanbyeol Kim, Jeongbae Park, Jeong-Mok Kim.
      Extensive progress in understanding the molecular mechanisms of cancer growth and proliferation has led to the remarkable development of drugs that target cancer-driving molecules. Most target molecules are proteins such as kinases and kinase-associated receptors, which have enzymatic activities needed for the signaling cascades of cells. The small molecule inhibitors for these target molecules greatly improved therapeutic efficacy and lowered the systemic toxicity in cancer therapies. However, long-term and high-dosage treatment of small inhibitors for cancer has produced other obstacles, such as resistance to inhibitors. Among recent approaches to overcoming drug resistance to cancers, targeted protein degradation (TPD) such as proteolysis-targeting chimera (PROTAC) technology adopts a distinct mechanism of action by which a target protein is destroyed through the cellular proteolytic system, such as the ubiquitin-proteasome system or autophagy. Here, we review the currently developed PROTACs as the representative TPD molecules for cancer therapy and the N-degrons of the N-degron pathways as the potential TPD ligands.
    Keywords:  N-degron; PROTAC; targeted cancer therapy
    DOI:  https://doi.org/10.3390/biomedicines10092100
  2. Autophagy. 2022 Sep 21. 1-16
    Autophagy is a novel pathway for neurofilament protein degradation in vivo.
    Mala V Rao, Sandipkumar Darji, Philip H Stavrides, Chris N Goulbourne, Asok Kumar, Dun-Sheng Yang, Lang Yoo, James Peddy, Ju-Hyun Lee, Aidong Yuan, Ralph A Nixon.
      How macroautophagy/autophagy influences neurofilament (NF) proteins in neurons, a frequent target in neurodegenerative diseases and injury, is not known. NFs in axons have exceptionally long half-lives in vivo enabling formation of large stable supporting networks, but they can be rapidly degraded during Wallerian degeneration initiated by a limited calpain cleavage. Here, we identify autophagy as a previously unrecognized pathway for NF subunit protein degradation that modulates constitutive and inducible NF turnover in vivo. Levels of NEFL/NF-L, NEFM/NF-M, and NEFH/NF-H subunits rise substantially in neuroblastoma (N2a) cells after blocking autophagy either with the phosphatidylinositol 3-kinase (PtdIns3K) inhibitor 3-methyladenine (3-MA), by depleting ATG5 expression with shRNA, or by using both treatments. In contrast, activating autophagy with rapamycin significantly lowers NF levels in N2a cells. In the mouse brain, NF subunit levels increase in vivo after intracerebroventricular infusion of 3-MA. Furthermore, using tomographic confocal microscopy, immunoelectron microscopy, and biochemical fractionation, we demonstrate the presence of NF proteins intra-lumenally within autophagosomes (APs), autolysosomes (ALs), and lysosomes (LYs). Our findings establish a prominent role for autophagy in NF proteolysis. Autophagy may regulate axon cytoskeleton size and responses of the NF cytoskeleton to injury and disease.
    Keywords:  3-MA; Con A; MG115; calpeptin; proteasome; rapamycin
    DOI:  https://doi.org/10.1080/15548627.2022.2124500
  3. Nat Biomed Eng. 2022 Sep;6(9): 1015-1016
    Non-invasive monitoring of autophagy.
    Ben Loos, Andre du Toit, Jan-Hendrik S Hofmeyr.
      
    DOI:  https://doi.org/10.1038/s41551-022-00943-w
  4. Trends Cell Biol. 2022 Sep 20. pii: S0962-8924(22)00208-2. [Epub ahead of print]
    Targeting of biomolecular condensates to the autophagy pathway.
    Xinyu Ma, Pilong Li, Liang Ge.
      Biomolecular condensates are membraneless compartments formed by liquid-liquid phase separation. They can phase transit into gel-like and solid states. The amount and state of biomolecular condensates must be tightly regulated to maintain normal cellular function. Autophagy targets biomolecular condensates to the lysosome for degradation or other purposes, which we term biocondensophagy. In biocondensophagy, autophagy receptors recognize biomolecular condensates and target them to the autophagosome, the vesicle carrier of autophagy. Multiple types of autophagy receptors have been identified and they are specifically involved in targeting biomolecular condensates with different phase transition states. The receptors also organize the phase transition of biomolecular condensate to facilitate biocondensophagy. Here, we briefly discuss the latest discoveries regarding how biomolecular condensates are recognized by autophagy receptors.
    Keywords:  aggrephagy; autophagy; autophagy receptor; biocondensophagy; biomolecular condensate; phase separation; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.006
  5. Biochemistry. 2022 Sep 21.
    Targeted Protein Degradation via Lysosomes.
    Rishi R Paudel, Dong Lu, Sandipan Roy Chowdhury, Erika Y Monroy, Jin Wang.
      In the scope of targeted protein degradation (TPD), proteolysis-targeting chimeras (PROTACs), leveraging the ubiquitin-proteasome system, have been extensively studied. However, they are limited to the degradation of soluble and membrane proteins, excluding the aggregated and extracellular proteins and dysfunctional organelles. As an alternative protein degradation pathway, lysosomes serve as a feasible tool for accessing these untouched proteins and/or organelles by proteosomes. Here, we focus on reviewing the emerging lysosome-mediated TPD, such as AUTAC, ATTEC, AUTOTAC, LYTAC, and MoDE-A. Intracellular targets, such as soluble and aggregated proteins and organelles, can be degraded via the autophagy-lysosome pathway. Extracellular targets, such as membrane proteins, and secreted extracellular proteins can be degraded via the endosome-lysosome pathway. In addition, we summarize the mechanism and regulation of autophagy, available methods and assays for monitoring the autophagy process, and the recently developed chemical probes for perturbing the autophagy pathways.
    DOI:  https://doi.org/10.1021/acs.biochem.2c00310
  6. Cell Death Differ. 2022 Sep 21.
    Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?
    Georg Häcker, Aladin Haimovici.
      One of the tasks of mitochondria is the rule over life and death: when the outer membrane is permeabilized, the release of intermembrane space proteins causes cell death by apoptosis. For a long time, this mitochondrial outer membrane permeabilization (MOMP) has been accepted as the famous step from which no cell returns. Recent results have however shown that this quite plainly does not have to be the case. A cell can also undergo only a little MOMP, and it can efficiently repair damage it has incurred in the process. There is no doubt now that such low-scale permeabilization occurs. A major unclarified issue is the biological relevance. Is small-scale mitochondrial permeabilization an accident, a leakiness of the apoptosis apparatus, perhaps during restructuring of the mitochondrial network? Is it attempted suicide, where cell death by apoptosis is the real goal but the stimulus failed to reach the threshold? Or, more boldly, is there a true biological meaning behind the event of the release of low amounts of mitochondrial components? We will here explore this last possibility, which we believe is on one hand appealing, on the other hand plausible and supported by some evidence. Recent data are consistent with the view that sub-lethal signals in the mitochondrial apoptosis pathway can drive inflammation, the first step of an immune reaction. The apoptosis apparatus is almost notoriously easy to trigger. Sub-lethal signals may be even easier to set off. We suggest that the apoptosis apparatus is used in this way to sound the call when the first human cell is infected by a pathogen.
    DOI:  https://doi.org/10.1038/s41418-022-01058-0
  7. Nat Commun. 2022 Sep 22. 13(1): 5550
    Protein condensation diseases: therapeutic opportunities.
    Michele Vendruscolo, Monika Fuxreiter.
      Condensed states of proteins, including liquid-like membraneless organelles and solid-like aggregates, contribute in fundamental ways to the organisation and function of the cell. Perturbations of these states can lead to a variety of diseases through mechanisms that we are now beginning to understand. We define protein condensation diseases as conditions caused by the disruption of the normal behaviour of the condensed states of proteins. We analyze the problem of the identification of targets for pharmacological interventions for these diseases and explore opportunities for the regulation of the formation and organisation of aberrant condensed states of proteins.
    DOI:  https://doi.org/10.1038/s41467-022-32940-7
  8. Front Oncol. 2022 ;12 1010222
    Editorial: Stress response signaling in tumor development and its implications for cancer treatment.
    Danwan Wen, Peng Zhao.
      
    Keywords:  cancer diagnosis; cancers; signaling transduction; stress response; therapeutic target and strategy
    DOI:  https://doi.org/10.3389/fonc.2022.1010222
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