bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2022‒08‒14
eleven papers selected by
Su Hyun Lee
Seoul National University

  1. Autophagy. 2022 Aug 10.
      Macroautophagy (hereafter "autophagy") is a membrane-mediated biological process that involves engulfing and delivering cytoplasmic components to lysosomes for degradation. In addition to autophagy's pro-survival effect during nutrient starvation, excessive activation of autophagy machinery can also cause regulated cell death, especially iron-dependent ferroptosis. Here, we report a key role for TMEM164 (transmembrane protein 164) in selectively mediating ATG5 (autophagy related 5)-dependent autophagosome formation during ferroptosis, rather than during starvation. In contrast, the membrane protein ATG9A (autophagy related 9A) is dispensable for the formation of autophagosomes during ferroptosis. TMEM164-mediated autophagy degrades ferritin, GPX4 (glutathione peroxidase 4), and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death. Consequently, the loss of TMEM164 limits the anticancer activity of ferroptosis-mediated cytotoxicity in mice. High TMEM164 expression is associated with improved survival and increased immune cell infiltration in patients with pancreatic cancer. These findings establish a new mode of autophagy-dependent ferroptosis.
    Keywords:  Autophagy; cell death; ferroptosis; membrane protein; tumor immunity
  2. Front Cell Dev Biol. 2022 ;10 947357
      Sirtuin 3, a member of the mammalian sirtuin family of proteins, is involved in the regulation of multiple processes in cells. It is a major mitochondrial NAD+-dependent deacetylase with a broad range of functions, such as regulation of oxidative stress, reprogramming of tumor cell energy pathways, and metabolic homeostasis. One of the intriguing functions of sirtuin 3 is the regulation of mitochondrial outer membrane permeabilization, a key step in apoptosis initiation/progression. Moreover, sirtuin 3 is involved in the execution of various cell death modalities, which makes sirtuin 3 a possible regulator of crosstalk between them. This review is focused on the role of sirtuin 3 as a target for tumor cell elimination and how mitochondria and reactive oxygen species (ROS) are implicated in this process.
    Keywords:  cell death modalities; mitochondria; reactive oxygen species; sirtuin; tumor elimination
  3. Trends Cell Biol. 2022 Aug 06. pii: S0962-8924(22)00175-1. [Epub ahead of print]
      The N-degron pathway is a degradative system in which the N-terminal residues of proteins modulate the half-lives of proteins and other cellular materials. The majority of amino acids in the genetic code have the potential to induce cis or trans degradation in diverse processes, which requires selective recognition between N-degrons and cognate N-recognins. Of particular interest is the Cys/N-degron branch, in which the N-terminal cysteine (Nt-Cys) induces proteolysis via either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome pathway (ALP), depending on physiological conditions. Recent studies provided new insights into the central role of Nt-Cys in sensing the fluctuating levels of oxygen and reactive oxygen species (ROS). Here, we discuss the components, regulations, and functions of the Cys/N-degron pathway.
    Keywords:  N-recognin; N-terminal oxidation; autophagy; oxygen sensor; proteolysis; the N-degron pathway
  4. Cells. 2022 Jul 28. pii: 2324. [Epub ahead of print]11(15):
      Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a "double-edged sword" that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and interacts with immune cells to modulate tumor immunotherapy. The discovery of autophagy inducers and autophagy inhibitors also provides new insights for clinical anti-tumor therapy. However, there are also difficulties in the application of autophagy-related regulators, such as low bioavailability and the lack of efficient selectivity. This review focuses on autophagy-related immunogenic regulation and its application in cancer therapy.
    Keywords:  autophagy; cancer therapy; immunity
  5. Autophagy. 2022 Aug 08. 1-2
      Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.
    Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy
  6. Autophagy. 2022 Aug 10.
      Genetic evidence has increasingly linked lysosome dysfunction to an impaired autophagy-lysosomal pathway (ALP) flux in Alzheimer disease (AD) although the relationship of these abnormalities to other pathologies is unclear. In our recent investigation on the origin of impaired autophagic flux in AD, we established the critical early role of defective lysosomes in 5 mouse AD models. To assess in vivo alterations of autophagy and ALP vesicle acidification, we expressed eGFP-mRFP-LC3 specifically in neurons. We discovered that autophagy dysfunction in these models arises from exceptionally early failure of autolysosome/lysosome acidification, which then drives downstream AD pathogenesis. Extreme autophagic stress in compromised but still intact neurons causes AVs containing toxic APP metabolites, Aβ/β-CTFs, to pack into huge blebs and protrude from the perikaryon membrane. Most notably, AVs also coalesce with ER tubules and yield fibrillar β-amyloid within these tubules. Collectively, amyloid immunoreactivity within these intact neurons assumes the appearance of amyloid-plaques and, indeed, their eventual death transforms them into extracellular plaque lesions. Quantitative analysis confirms that neurons undergoing this transformation are the principal source of β-amyloid-plaques in APP-AD models. These findings prompt reconsideration of the conventionally accepted sequence of events in plaque formation and may help explain the inefficacy of Aβ/amyloid vaccine therapies.
    Keywords:  APP-βCTF; Alzheimer’s disease; Aβ; LC3; acidification; autophagy; lysosome; neuritic plaque; perikaryal blebbing
  7. Cell Biosci. 2022 Aug 12. 12(1): 126
      Ubiquitination is a versatile post-translational modification (PTM), which regulates diverse fundamental features of protein substrates, including stability, activity, and localization. Unsurprisingly, dysregulation of the complex interaction between ubiquitination and deubiquitination leads to many pathologies, such as cancer and neurodegenerative diseases. The versatility of ubiquitination is a result of the complexity of ubiquitin (Ub) conjugates, ranging from a single Ub monomer to Ub polymers with different length and linkage types. To further understand the molecular mechanism of ubiquitination signaling, innovative strategies are needed to characterize the ubiquitination sites, the linkage type, and the length of Ub chain. With advances in chemical biology tools, computational methodologies, and mass spectrometry, protein ubiquitination sites and their Ub chain architecture have been extensively revealed. The obtained information on protein ubiquitination helps to crack the molecular mechanism of ubiquitination in numerous pathologies. In this review, we summarize the recent advances in protein ubiquitination analysis to gain updated knowledge in this field. In addition, the current and future challenges and barriers are also reviewed and discussed.
    Keywords:  Deubiquitination; Mass spectrometry; Post-translational modification; Ubiquitination
  8. Curr Med Chem. 2022 Aug 11.
      The process by which cells selectively remove damaged organelles or proteins is called autophagy. Chaperone-mediated autophagy (CMA) is a type of autophagy that degrades proteins containing the KFERQ pentapeptide in cells. CMA can degrade damaged or excess proteins and therefore plays an important role in maintaining protein balance in cells. CMA can also play a regulatory role by degrading key proteins in life activities, such as lipid and glucose metabolism. In this review, we introduce the CMA process and described the current commonly used CMA detection methods. In addition, we describe the role of CMA in glucose and lipid metabolism. Finally, we summarize the current role of CMA in metabolic diseases such as diabetic nephropathy (DN), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) and discuss the role of CMA as a potential therapeutic target for metabolic diseases.
    Keywords:  Autophagy; Chaperone-mediated autophagy (CMA); Diabetic nephropathy (DN); HSC70; LAMP2A; Metabolic diseases
  9. Cancers (Basel). 2022 Aug 03. pii: 3778. [Epub ahead of print]14(15):
      Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022.
    Keywords:  LYTAC; PROTAC; autophagy; chaperone-mediated autophagy; endoplasmic reticulum stress; heat shock proteins; hematological malignancies; macroautophagy; unfolded protein response
  10. Life Sci. 2022 Aug 07. pii: S0024-3205(22)00570-7. [Epub ahead of print] 120870
      Sirtuins perform an important effect on the neural cell fate following stroke. Several mechanisms that have been correlated with stroke are oxidative stress, apoptosis, necrosis and autophagy. Autophagy is usually regarded as unitary of the neural cell survival mechanisms. Recently, the importance of the sirtuins effect on autophagy by antioxidant agents for stroke treatment mentioned in various studies. One of these agents is melatonin. Melatonin can modulate autophagy by changing on sirtuin pathways. Melatonin and its metabolites adjust various sirtuins pathways related to apoptosis, proliferation, metastases, autophagy and inflammation in case of stroke. In this review, we will discuss about the modulation of autophagy by melatonin via sirtuins in stroke.
    Keywords:  Autophagy; Cerebrovascular disease; Melatonin; Sirtuins; Stroke
  11. Cell Death Dis. 2022 Aug 08. 13(8): 692
      Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified the Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the antiapoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of apoptotic regulators that bind to SMAC and LATS1. Mechanistic analysis shows that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results in apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the proapoptotic signal mediated by the LATS1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes the formation of this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant, which requires C-IAP1 inhibition and the degradation of XIAP, suggesting that the MST2 pathway is part of the mechanism of action of Birinapant. Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway.