bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023–07–09
seven papers selected by
Su Hyun Lee, Harvard University



  1. Mol Cell. 2023 Jul 06. pii: S1097-2765(23)00464-1. [Epub ahead of print]83(13): 2159-2160
      Most methods for targeted protein degradation (TPD) deliver targets to E3 ubiquitin ligases, leading to proteasomal degradation. In this issue of Molecular Cell, Shaaban et al.1 illuminate cullin-RING ubiquitin ligase (CRL) modulation by CAND1, which can be utilized for TPD.
    DOI:  https://doi.org/10.1016/j.molcel.2023.06.017
  2. EMBO J. 2023 Jul 06. e113348
      UBR5 is a nuclear E3 ligase that ubiquitinates a vast range of substrates for proteasomal degradation. This HECT domain-containing ubiquitin ligase has recently been identified as an important regulator of oncogenes, e.g., MYC, but little is known about its structure or mechanisms of substrate engagement and ubiquitination. Here, we present the cryo-EM structure of human UBR5, revealing an α-solenoid scaffold with numerous protein-protein interacting motifs, assembled into an antiparallel dimer that adopts further oligomeric states. Using cryo-EM processing tools, we observe the dynamic nature of the UBR5 catalytic domain, which we postulate is important for its enzymatic activity. We characterise the proteasomal nuclear import factor AKIRIN2 as an interacting protein and propose UBR5 as an efficient ubiquitin chain elongator. This preference for ubiquitinated substrates and several distinct domains for protein-protein interactions may explain how UBR5 is linked to several different signalling pathways and cancers. Together, our data expand on the limited knowledge of the structure and function of HECT E3 ligases.
    Keywords:  HECT; UBR5; Ubiquitin-Proteasome system; cryo-EM
    DOI:  https://doi.org/10.15252/embj.2022113348
  3. Autophagy. 2023 Jul 07. 1-19
      Apoptosis is a tightly controlled cell death program executed by proteases, the so-called caspases. It plays an important role in tissue homeostasis and is often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end-directed transport of autophagic and endosomal vesicles as a molecular interaction partner of activated CASP8 (caspase 8). The absence of FYCO1 sensitized cells to basal and TNFSF10/TRAIL-induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC). Loss of FYCO1 resulted in impaired transport of TNFRSF10B/TRAIL-R2/DR5 (TNF receptor superfamily member 10b) to the lysosomes in TNFSF10/TRAIL-stimulated cells. More in detail, we show that FYCO1 interacted via its C-terminal GOLD domain with the CCZ1-MON1A complex, which is necessary for RAB7A activation and for the fusion of autophagosomal/endosomal vesicles with lysosomes. We demonstrated that FYCO1 is a novel and specific CASP8 substrate. The cleavage at aspartate 1306 resulted in the release of the C-terminal GOLD domain, inactivating FYCO1 function, and allowing for the progression of apoptosis. Furthermore, the lack of FYCO1 resulted in a stronger and prolonged formation of the TNFRSF1A/TNF-R1 signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a control mechanism that fine-tunes both apoptotic and inflammatory answers.Abbreviations: AP: affinity purification; CHX: cycloheximide; co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DISC: death-inducing signaling complex; DR: death receptors; doxy: doxycycline; GEF: guanine nucleotide exchange factor; ind: inducible; KD: knockdown; KO: knockout; MS: mass spectrometry; shRNA: short hairpin RNA; siRNA: small interfering RNA; TIP: two-step co-immunoprecipitation; WB: western blot.
    Keywords:  FYCO1; TRAIL; apoptosis; autophagy; caspase 8; lysosomal degradation
    DOI:  https://doi.org/10.1080/15548627.2023.2229656
  4. Signal Transduct Target Ther. 2023 Jul 07. 8(1): 263
      Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.
    DOI:  https://doi.org/10.1038/s41392-023-01458-9
  5. Nat Commun. 2023 Jul 06. 14(1): 3997
      Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca2+ channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.
    DOI:  https://doi.org/10.1038/s41467-023-39716-7
  6. Cell Death Dis. 2023 Jul 06. 14(7): 402
      Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.
    DOI:  https://doi.org/10.1038/s41419-023-05915-9
  7. Front Oncol. 2023 ;13 1220435
       Objective: The purpose of this study was to analyze the trends by year, country, institution, journal, reference and keyword in publications on the autophagy of pancreatic cancer (PC) and to predict future research hotspots.
    Methods: The Web of Science Core Collection was used to search for publications. The contributions of various countries/regions, institutes, authors, identified research hotspots, and promising future trends were analyzed using the VOSviewer1.6.16 and CiteSpace6.6.R2 programs. We also summarized autophagy relevant clinical trials of PC.
    Results: A total of 1293 papers on the autophagy of PC published between 2013 and 2023 were included in the study. The average number of citations per article was 33.76. The China had the most publications, followed by USA, and a total of 50 influential articles were identified through co-citation analysis. Clustering analysis revealed clusters of keywords: metabolic reprogramming and ER stress, mTOR-mediated apoptosis, extracellular trap as the most concerned clusters. The co-occurrence cluster analysis showed pancreatic stellate cell, autophagy-dependent ferroptosis, autophagy-related pathway, metabolic rewiring, on-coding RNA as the highly concerned research topics in recently.
    Conclusion: The number of publications and research interest have generally increased over the past few years. The China and USA have made prominent contributions to the study of the autophagy of PC. The current research hotspots mainly focus not only on the related modulation, metabolic reprogramming, ferroptosis of tumor cells themselves, but also on tumor microenvironments such as autophagy associated pancreatic stellate cells and new treatments targeting autophagy.
    Keywords:  autophagy; bibliometric study; ferroptosis; pancreatic cancer; pancreatic stellate cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1220435