bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023‒03‒12
six papers selected by
Su Hyun Lee
Harvard University
  1. TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
  2. The autophagy-NAD axis in longevity and disease.
  3. A novel role of ATG9A and RB1CC1/FIP200 in mediating cell-death checkpoints to repress TNF cytotoxicity.
  4. A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
  5. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy.
  6. STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.
  1. Mol Cell. 2023 Mar 02. pii: S1097-2765(23)00150-8. [Epub ahead of print]
    TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
    François Le Guerroué, Eric N Bunker, William M Rosencrans, Jack T Nguyen, Mohammed A Basar, Achim Werner, Tsui-Fen Chou, Chunxin Wang, Richard J Youle.
      Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates mitophagy rates and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with autophagy receptors, which provides a molecular rationale for its inhibitory function during mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis.
    Keywords:  FIP200; FIR; LIR; Selective autophagy; TAX1BP1; TBK1; TNIP1; mitophagy; mitophagy regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.023
  2. Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]
    The autophagy-NAD axis in longevity and disease.
    Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
    Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
  3. Autophagy. 2023 Mar 09. 1-2
    A novel role of ATG9A and RB1CC1/FIP200 in mediating cell-death checkpoints to repress TNF cytotoxicity.
    Ying Yang, Daniel J Klionsky.
      TNF (tumor necrosis factor) is an important cytokine that regulates immune responses in response to microbial infection. Two fates can be induced by TNF sensing, including activation of NFKB/NF-κB and cell death, which are mainly regulated by the formation of TNFRSF1A/TNFR1 (TNF receptor superfamily member 1A) complex I and complex II, respectively. Abnormal TNF-induced cell death leads to detrimental outcomes, underlying several human inflammatory diseases. The actions of "protective brakes", or so-called specific "cell death checkpoints", are important to prevent TNF cytotoxicity. A recent study published in Science characterizes novel functions of ATG9A, RB1CC1/FIP200 and TAX1BP1 as components of a previously undiscovered TNF-induced cell death checkpoint, independent of its roles in canonical macroautophagy/autophagy. Notably, this ATG9A-controlled cell-death checkpoint contributes to the prevention of inflammatory skin disease, demonstrating its crucial role in serving as a safeguard against the threat of TNF cytotoxicity.
    Keywords:  Autophagy; ULK1 kinase complex; inflammation; skin disease; tumor necrosis factor
    DOI:  https://doi.org/10.1080/15548627.2023.2187609
  4. EMBO J. 2023 Mar 10. e113033
    A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
    Yu Cao, Jing Zheng, Huayun Wan, Yuqiu Sun, Song Fu, Shanshan Liu, Baiyu He, Gaihong Cai, Yang Cao, Huanwei Huang, Qi Li, Yan Ma, She Chen, Fengchao Wang, Hui Jiang.
      Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.
    Keywords:  BNIP3/NIX; FBXL4; mitochondrial disease; mitophagy; ubiquitin-proteasome pathway
    DOI:  https://doi.org/10.15252/embj.2022113033
  5. Clin Transl Med. 2023 Mar;13(3): e1204
    The roles of E3 ubiquitin ligases in cancer progression and targeted therapy.
    Chibuzo Sampson, Qiuping Wang, Wuxiyar Otkur, Haifeng Zhao, Yun Lu, Xiaolong Liu, Hai-Long Piao.
      Ubiquitination is one of the most important post-translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.
    Keywords:  E3 ubiquitin ligases; cancer; targeted therapy; ubiquitination
    DOI:  https://doi.org/10.1002/ctm2.1204
  6. EMBO J. 2023 Mar 06. e112387
    STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.
    Wei Wan, Chuying Qian, Qian Wang, Jin Li, Hongtao Zhang, Lei Wang, Maomao Pu, Yewei Huang, Zhengfu He, Tianhua Zhou, Han-Ming Shen, Wei Liu.
      The cGAS-STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS-STING pathway-induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING-induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P-binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. Furthermore, we show that the STING-WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS-STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.
    Keywords:  STING; WIPI2; autophagy; cGAS; cytoplasmic DNA
    DOI:  https://doi.org/10.15252/embj.2022112387
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