bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2021–10–17
seven papers selected by
Su Hyun Lee, Seoul National University
  1. Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53.
  2. Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates.
  3. The necessity of nucleophagic modality.
  4. A new type of membrane contact in the ER-Golgi system regulates autophagosome biogenesis.
  5. EIF4A3: a gatekeeper of autophagy.
  6. Prefused lysosomes cluster on autophagosomes regulated by VAMP8.
  7. The ubiquitin-proteasome system in normal hearing and deafness.
  1. Cell Death Dis. 2021 Oct 14. 12(10): 945
    Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53.
    Yafei Guo, Qin Li, Gang Zhao, Jie Zhang, Hang Yuan, Tianyu Feng, Deqiong Ou, Rui Gu, Siqi Li, Kai Li, Ping Lin.
      Breast cancer is the most common cancer in the world. Relapse and metastasis are important factors endangering the life of breast cancer patients, but the mechanism is still unclear. The stabilization of p53 is essential for preventing carcinogenesis, and ubiquitination is one of the main ways to regulate the stability of p53. Tripartite motif-containing 31 (TRIM31) is a new member of the TRIM family and functions as an E3 ubiquitin ligase. It acts as a cancer promoter or suppressor in the malignant processes of multiple cancers. However, the function of TRIM31 in breast cancer progression remains unknown. In this study, we showed that TRIM31 is downregulated in breast cancer tissues and negatively correlated with breast cancer progression. Both gain- and loss-of-function assays indicated that TRIM31 inhibits the proliferation, colony formation, migration, and invasion of breast cancer cells. Further investigation demonstrated that TRIM31 directly interacts with p53, and inducing the K63-linked ubiquitination of p53 via its RING domain, Meanwhile, TRIM31 suppresses the MDM2-mediated K48-linked ubiquitination of p53 through competitive inhibiting the interaction of MDM2 and p53, leading to the p53 stabilization and activation. Knockdown of p53 reversed the inhibitory effects of TRIM31 on the growth and metastasis of breast cancer cells. Moreover, we found that the RING and coiled-coil (C-C) domains of TRIM31 were essential for its tumor suppressor function. Taken together, our findings reveal a novel mechanism by which TRIM31 suppresses breast cancer development through the stabilization and activation of p53 and define a promising therapeutic strategy for restoring TRIM31 to treat breast cancer.
    DOI:  https://doi.org/10.1038/s41419-021-04208-3
  2. Nat Commun. 2021 Oct 13. 12(1): 5989
    Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates.
    Shuang-Zhou Peng, Xiao-Hui Chen, Si-Jie Chen, Jie Zhang, Chuan-Ying Wang, Wei-Rong Liu, Duo Zhang, Ying Su, Xiao-Kun Zhang.
      Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.
    DOI:  https://doi.org/10.1038/s41467-021-26295-8
  3. Autophagy. 2021 Oct 13. 1-6
    The necessity of nucleophagic modality.
    Dalibor Mijaljica, Daniel J Klionsky.
      Nucleophagy, the selective subtype of autophagy that predominantly targets only a selected and (nonessential) portion of the nucleus, and rarely the nucleus in its entirety, for degradation, reinforces the paradigm that nucleophagy recycling is a meticulous and highly delicate process guarded by fail-safe mechanisms. Our goal in this commentary is to encourage autophagy researchers and other scientists to explore nucleophagy blind spots and gain advanced insights into the diverse roles of this process and its selective modality as they pertain to intranuclear quality control and cellular homeostasis. Identifying and deciphering nucleophagic signaling, regulation, molecular mechanism(s) and its mediators, cargo composition and nuclear membrane dynamics under numerous physiological and/or pathological settings will provide important advances in our understanding of this critical type of organelle-selective autophagy.Abbreviations: INM, inner nuclear membrane; LN, late nucleophagy; mRNA, messenger RNA; NE, nuclear envelope; NL, nuclear lamina; NPC(s), nuclear pore complex(es); NVJ(s), nucleus-vacuole junction(s); ONM, outer nuclear membrane; PMN, piecemeal microautophagy of the nucleus; PND, programmed nuclear death; PNuD, programmed nuclear destruction; rDNA/rRNA, ribosomal DNA/RNA.
    Keywords:  Cargo; degradation; homeostasis; macronucleophagy; membrane; micronucleophagy; mode; nucleophagy; nucleus; vacuole
    DOI:  https://doi.org/10.1080/15548627.2021.1971380
  4. Autophagy. 2021 Oct 13. 1-3
    A new type of membrane contact in the ER-Golgi system regulates autophagosome biogenesis.
    Shulin Li, Min Zhang, Liang Ge.
      Formation of the double-membrane autophagosome requires membrane reorganization of the endomembrane system to generate membrane precursors. The ER-Golgi trafficking system has been shown to provide membranes for phagophore growth. Nonetheless, how the components of the ER-Golgi system are redirected toward autophagosome biogenesis remains unclear. Here, we identify a new type of membrane contact formed between the ER-Golgi intermediate compartment (ERGIC) and the ER-exit sites (ERES) under macroautophagy/autophagy-induction conditions. The ERGIC-ERES contact is established by the TMED9-PREB/SEC12 interaction and regulates the biogenesis of the ERGIC-COPII vesicles, which we found previously act as a membrane template for LC3 lipidation and autophagosome formation.
    Keywords:  Autophagosome; COPII; ERES; ERGIC; SEC12; TMED9; autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1972406
  5. Autophagy. 2021 Oct 13. 1-2
    EIF4A3: a gatekeeper of autophagy.
    Despoina Sakellariou, Lisa B Frankel.
      EIF4A3 (eukaryotic translation initiation factor 4A3) is an RNA helicase and core component of the exon junction complex. While this RNA-binding protein (RBP) is well-characterized for its crucial roles in splicing, RNA trafficking and nonsense-mediated decay, its role in the regulation of metabolic signaling pathways remains elusive. In a recent study, we describe a new role for EIF4A3 as a negative regulator of macroautophagy/autophagy. Mechanistically, we report that EIF4A3, through its ability to safeguard splicing, can maintain low basal levels of autophagy through the cytosolic retention of the key autophagy transcription factor TFEB. Upon EIF4A3 depletion, the shuttling of TFEB to the nucleus results in an integrated transcriptional response, which induces both early and late steps of the autophagy pathway and enhances autophagic flux. We further report the upregulation of EIF4A3 across multiple cancer types and highlight the relevance of this newly identified EIF4A3-TFEB signaling axis in human tumors.
    Keywords:  Autophagy regulation; EIF4A3; GSK3B; RNA-binding proteins; TFEB; cancer; exon skipping
    DOI:  https://doi.org/10.1080/15548627.2021.1985881
  6. Cell Death Dis. 2021 Oct 13. 12(10): 939
    Prefused lysosomes cluster on autophagosomes regulated by VAMP8.
    Qixin Chen, Mingang Hao, Lei Wang, Linsen Li, Yang Chen, Xintian Shao, Zhiqi Tian, Richard A Pfuetzner, Qing Zhong, Axel T Brunger, Jun-Lin Guan, Jiajie Diao.
      Lysosome-autophagosome fusion is critical to autophagosome maturation. Although several proteins that regulate this fusion process have been identified, the prefusion architecture and its regulation remain unclear. Herein, we show that upon stimulation, multiple lysosomes form clusters around individual autophagosomes, setting the stage for membrane fusion. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein on lysosomes-vesicle-associated membrane protein 8 (VAMP8)-plays an important role in forming this prefusion state of lysosomal clusters. To study the potential role of phosphorylation on spontaneous fusion, we investigated the effect of phosphorylation of C-terminal residues of VAMP8. Using a phosphorylation mimic, we observed a decrease of fusion in an ensemble lipid mixing assay and an increase of unfused lysosomes associated with autophagosomes. These results suggest that phosphorylation not only reduces spontaneous fusion for minimizing autophagic flux under normal conditions, but also preassembles multiple lysosomes to increase the fusion probability for resuming autophagy upon stimulation. VAMP8 phosphorylation may thus play an important role in chemotherapy drug resistance by influencing autophagosome maturation.
    DOI:  https://doi.org/10.1038/s41419-021-04243-0
  7. Hear Res. 2021 Sep 29. pii: S0378-5955(21)00200-8. [Epub ahead of print] 108366
    The ubiquitin-proteasome system in normal hearing and deafness.
    Ronald Pouyo, Keshi Chung, Laurence Delacroix, Brigitte Malgrange.
      Post-translational modifications of proteins are essential for the proper development and function of many tissues and organs, including the inner ear. Ubiquitination is a highly selective post-translational modification that involves the covalent conjugation of ubiquitin to a substrate protein. The most common outcome of protein ubiquitination is degradation by the ubiquitin-proteasome system (UPS), preventing the accumulation of misfolded, damaged, and excess proteins. In addition to proteasomal degradation, ubiquitination regulates other cellular processes, such as transcription, translation, endocytosis, receptor activity, and subcellular localization. All of these processes are essential for cochlear development and maintenance, as several studies link impairment of UPS with altered cochlear development and hearing loss. In this review, we provide insight into the well-oiled machinery of UPS with a focus on its confirmed role in normal hearing and deafness and potential therapeutic strategies to prevent and treat UPS-associated hearing loss.
    Keywords:  ARHL; Cochlea; Deafness; Development; UPS
    DOI:  https://doi.org/10.1016/j.heares.2021.108366
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