bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–09–15
sixteen papers selected by
William Grey, University of York
  1. USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression.
  2. Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.
  3. Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.
  4. Macrophages and hematopoietic stem cells teach us that sharing is caring.
  5. The role of the haematopoietic stem cell niche in development and ageing.
  6. Proteomic characterization of murine hematopoietic stem progenitor cells reveals dynamic fetal-to-adult changes in metabolic-related pathways.
  7. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets.
  8. p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation.
  9. CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.
  10. Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation.
  11. TRIM44, a Novel Prognostic Marker, Supports the Survival of Proteasome-Resistant Multiple Myeloma Cells.
  12. Protocol for detecting lysosome quantity and membrane permeability in acute myeloid leukemia cell lines.
  13. Deletion of the foxO1 gene reduces hypoxia tolerance in zebrafish embryos by influencing erythropoiesis.
  14. CXCR4 as a therapeutic target in acute myeloid leukemia.
  15. A novel prognostic model based on pyroptosis signature in AML.
  16. Cytosolic FKBPL and ER-resident CKAP4 co-regulates ER-phagy and protein secretion.
  1. Leukemia. 2024 Sep 12.
    USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression.
    Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao, Xiang Cheng, Qingyuan Sun, Zhenyu Ju.
      Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.
    DOI:  https://doi.org/10.1038/s41375-024-02338-z
  2. Science. 2024 Sep 13. 385(6714): eadn1629
    Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.
    Cecilia Pessoa Rodrigues, Joseph M Collins, Song Yang, Catherine Martinez, Ji Wook Kim, Chhiring Lama, Anna S Nam, Clemens Alt, Charles Lin, Leonard I Zon.
      Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an "eat-me" signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial "don't eat-me" signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance. Whole-genome CRISPR-Cas9 screening showed that Toll-like receptor 3 (Tlr3) signaling regulated b2m expression. Targeting b2m or tlr3 reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive element (RE) transcripts. Overall, our data suggest that RE-associated double-stranded RNA could interact with TLR3 to stimulate surface expression of B2m on hematopoietic stem and progenitor cells. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.
    DOI:  https://doi.org/10.1126/science.adn1629
  3. Cancer Res. 2024 Sep 12.
    Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.
    Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang.
      Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating pre-leukemic clones, here we used a conditional Runx1::Runx1t1 knock-in mouse model to evaluate pre-leukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these pre-leukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3861
  4. Nat Cardiovasc Res. 2024 Sep;3(9): 1020
    Macrophages and hematopoietic stem cells teach us that sharing is caring.
    Gerburg Schwaerzer.
      
    DOI:  https://doi.org/10.1038/s44161-024-00541-w
  5. Nat Rev Mol Cell Biol. 2024 Sep 10.
    The role of the haematopoietic stem cell niche in development and ageing.
    Terri L Cain, Marta Derecka, Shannon McKinney-Freeman.
      Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.
    DOI:  https://doi.org/10.1038/s41580-024-00770-8
  6. Biochem Biophys Res Commun. 2024 Sep 04. pii: S0006-291X(24)01197-5. [Epub ahead of print]734 150661
    Proteomic characterization of murine hematopoietic stem progenitor cells reveals dynamic fetal-to-adult changes in metabolic-related pathways.
    Yanyu Xiu, Mingfang Xiong, Haoyu Yang, Qianqian Wang, Xiao Zhao, Juan Long, Fei Liang, Nan Liu, Fudong Chen, Meng Gao, Yuying Sun, Ruiwen Fan, Yang Zeng.
      Hematopoietic stem progenitor cells (HSPCs) give rise to the hematopoietic system, maintain hematopoiesis throughout the lifespan, and undergo molecular and functional changes during their development and aging. The importance of hematopoietic stem cell (HSC) biology has led to their extensive characterization at genomic and transcriptomic levels. However, the proteomics of HSPCs throughout the murine lifetime still needs to be fully completed. Here, using mass spectrometry (MS)-based quantitative proteomics, we report on the dynamic changes in the proteome of HSPCs from four developmental stages in the fetal liver (FL) and the bone marrow (BM), including E14.5, young (2 months), middle-aged (8 months), and aging (18 months) stages. Proteomics unveils highly dynamic protein kinetics during the development and aging of HSPCs. Our data identify stage-specific developmental features of HSPCs, which can be linked to their functional maturation and senescence. Our proteomic data demonstrated that FL HSPCs depend on aerobic respiration to meet their proliferation and oxygen supply demand, while adult HSPCs prefer glycolysis to preserve the HSC pool. By functional assays, we validated the decreased mitochondrial metabolism, glucose uptake, reactive oxygen species (ROS) production, protein synthesis rate, and increased glutathione S-transferase (GST) activity during HSPC development from fetal to adult. Distinct metabolism pathways and immune-related pathways enriched in different HSPC developmental stages were revealed at the protein level. Our study will have broader implications for understanding the mechanism of stem cell maintenance and fate determination and reversing the HSC aging process.
    Keywords:  Glutathione (GSH); HSC aging; Hematopoietic stem progenitor cells (HSPCs); Metabolism; Proteomics
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150661
  7. Nat Commun. 2024 Sep 11. 15(1): 7966
    Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets.
    Tsu-Yi Su, Julia Hauenstein, Ece Somuncular, Özge Dumral, Elory Leonard, Charlotte Gustafsson, Efthymios Tzortzis, Aurora Forlani, Anne-Sofie Johansson, Hong Qian, Robert Månsson, Sidinh Luc.
      Age is a risk factor for hematologic malignancies. Attributes of the aging hematopoietic system include increased myelopoiesis, impaired adaptive immunity, and a functional decline of the hematopoietic stem cells (HSCs) that maintain hematopoiesis. Changes in the composition of diverse HSC subsets have been suggested to be responsible for age-related alterations, however, the underlying regulatory mechanisms are incompletely understood in the context of HSC heterogeneity. In this study, we investigated how distinct HSC subsets, separated by CD49b, functionally and molecularly change their behavior with age. We demonstrate that the lineage differentiation of both lymphoid-biased and myeloid-biased HSC subsets progressively shifts to a higher myeloid cellular output during aging. In parallel, we show that HSCs selectively undergo age-dependent gene expression and gene regulatory changes in a progressive manner, which is initiated already in the juvenile stage. Overall, our studies suggest that aging intrinsically alters both cellular and molecular properties of HSCs.
    DOI:  https://doi.org/10.1038/s41467-024-52318-1
  8. Nat Commun. 2024 Sep 06. 15(1): 7787
    p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation.
    Clyde A Campbell, Rodolfo Calderon, Giulia Pavani, Xiaoyi Cheng, Radwa Barakat, Elizabeth Snella, Fang Liu, Xiyu Peng, Jeffrey J Essner, Karin S Dorman, Maura McGrail, Paul Gadue, Deborah L French, Raquel Espin-Palazon.
      Most gene functions have been discovered through phenotypic observations under loss of function experiments that lack temporal control. However, cell signaling relies on limited transcriptional effectors, having to be re-used temporally and spatially within the organism. Despite that, the dynamic nature of signaling pathways have been overlooked due to the difficulty on their assessment, resulting in important bottlenecks. Here, we have utilized the rapid and synchronized developmental transitions occurring within the zebrafish embryo, in conjunction with custom NF-kB reporter embryos driving destabilized fluorophores that report signaling dynamics in real time. We reveal that NF-kB signaling works as a clock that controls the developmental progression of hematopoietic stem and progenitor cells (HSPCs) by two p65 activity waves that inhibit cell cycle. Temporal disruption of each wave results in contrasting phenotypic outcomes: loss of HSPCs due to impaired specification versus proliferative expansion and failure to delaminate from their niche. We also show functional conservation during human hematopoietic development using iPSC models. Our work identifies p65 as a previously unrecognized contributor to cell cycle regulation, revealing why and when pro-inflammatory signaling is required during HSPC development. It highlights the importance of considering and leveraging cell signaling as a temporally dynamic entity.
    DOI:  https://doi.org/10.1038/s41467-024-51922-5
  9. bioRxiv. 2024 Aug 27. pii: 2024.08.26.609725. [Epub ahead of print]
    CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.
    Donovan Drouillard, Michael Halyko, Elizabeth Cinquegrani, Donna McAllister, Francis C Peterson, Adriano Marchese, Michael B Dwinell.
      Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors mobilize AML cells into the bloodstream where they become more chemosensitive have failed to improve patient survival, likely reflecting persistent receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the dimeric CXCL12 structure. CXCL12-LD binding resulted in lower levels of G protein, β-arrestin, and intracellular calcium mobilization, consistent with the locked dimer being a partial agonist of CXCR4. Further, CXCL12-LD failed to induce chemotaxis in AML cells. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wildtype and locked-monomer forms of CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in chemoresistance and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist signaling can avoid pharmacodynamic tolerance and may identify new avenues to better target GPCRs.
    Keywords:  Acute Myeloid Leukemia; CXCR4; Chemokines; GPCR; cell signaling; receptor internalization
    DOI:  https://doi.org/10.1101/2024.08.26.609725
  10. Elife. 2024 Sep 13. pii: RP87935. [Epub ahead of print]12
    Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation.
    Jiansen Lu, Jiahuan Zhang, Huaji Jiang, Zhiqiang Hu, Yufen Zhang, Lian He, Jianwu Yang, Yingchao Xie, Dan Wu, Hongyu Li, Ke Zeng, Peng Tan, Qingyue Xiao, Zijing Song, Chenglong Pan, Xiaochun Bai, Xiao Yu.
      Van Gogh-like 2 (Vangl2), a core planar cell polarity component, plays an important role in polarized cellular and tissue morphology induction, growth development, and cancer. However, its role in regulating inflammatory responses remains elusive. Here, we report that Vangl2 is upregulated in patients with sepsis and identify Vangl2 as a negative regulator of The nuclear factor-kappaB (NF-κB) signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 (Vangl2ΔM) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of proinflammatory cytokines after LPS stimulation. Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.
    Keywords:  NF-κB signaling; PDLIM2; Vangl2; human; immunology; inflammation; mouse; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.7554/eLife.87935
  11. Cells. 2024 Aug 26. pii: 1431. [Epub ahead of print]13(17):
    TRIM44, a Novel Prognostic Marker, Supports the Survival of Proteasome-Resistant Multiple Myeloma Cells.
    Trung Vu, Yuqin Wang, Annaliese Fowler, Anton Simieou, Nami McCarty.
      TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.
    Keywords:  autophagy; multiple myeloma; unfolded protein response
    DOI:  https://doi.org/10.3390/cells13171431
  12. STAR Protoc. 2024 Sep 12. pii: S2666-1667(24)00474-X. [Epub ahead of print]5(3): 103309
    Protocol for detecting lysosome quantity and membrane permeability in acute myeloid leukemia cell lines.
    Kexiu Huang, Xinya Jiang, Juan Du, Hui Zeng.
      Lysosomal function and activity are essential to support cellular adaptation to multiple stresses. For example, certain drugs can induce increased lysosomal membrane permeability to exert their anti-cancer effects. Here, we present a protocol to evaluate the lysosome alterations induced by drug treatment. We first describe the steps for inducing lysosomal alterations in cultured cells. We then show how to quantify the number of lysosomes, assess the integrity of lysosomal membranes, and determine lysosomal membrane permeabilization by using galectin puncta assay. For complete details on the use and execution of this protocol, please refer to Jiang et al.1.
    Keywords:  cancer; cell biology; cell culture; flow cytometry
    DOI:  https://doi.org/10.1016/j.xpro.2024.103309
  13. Life Sci. 2024 Sep 11. pii: S0024-3205(24)00638-6. [Epub ahead of print] 123048
    Deletion of the foxO1 gene reduces hypoxia tolerance in zebrafish embryos by influencing erythropoiesis.
    Lin-Lin Shi, Ke Ye, Su-Zhen Wang, Chao-Jie Hou, A-Kang Song, Hong Liu, Huan-Ling Wang.
      FoxO1 (Forkhead box O1) belongs to the evolutionarily conserved FoxO subfamily and is involved in diverse physiologic processes, including apoptosis, cell cycle, DNA damage repair, oxidative stress and cell differentiation. FoxO1 plays an important role in regulating the hypoxia microenvironment such as cancers, but its role in hypoxia adaptation remains unclear in animals. To understand the function of foxO1 in hypoxia response, we constructed foxO1a and foxO1b mutant zebrafish using CRISPR/Cas9 technology. It was found that foxO1a and foxO1b destruction affected the hematopoietic system in the early zebrafish embryos. Specifically, FoxO1a and FoxO1b were found to affect the transcriptional activity of runx1, a marker gene for hematopoietic stem cells (HSCs). Moreover, foxO1a and foxO1b had complementary features in hypoxia response, and foxO1a or/and foxO1b destruction resulted in tolerance of zebrafish becoming weakened in hypoxia due to insufficient hemoglobin supply. Additionally, the transcriptional activity of these two genes was demonstrated to be regulated by Hif1α. In conclusion, foxO1a and foxO1b respond to Hif1α-mediated hypoxia response by participating in zebrafish erythropoiesis. These results will provide a theoretical basis for further exploring the function of FoxO1 in hematopoiesis and hypoxia response.
    Keywords:  Erythropoiesis; Hematopoiesis; Hypoxia; Zebrafish; foxO1a; foxO1b
    DOI:  https://doi.org/10.1016/j.lfs.2024.123048
  14. Leukemia. 2024 Sep 11.
    CXCR4 as a therapeutic target in acute myeloid leukemia.
    Jan Korbecki, Mateusz Bosiacki, Patrycja Kupnicka, Katarzyna Barczak, Dariusz Chlubek, Irena Baranowska-Bosiacka.
      Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML's oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and Treg cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.
    DOI:  https://doi.org/10.1038/s41375-024-02326-3
  15. Heliyon. 2024 Sep 15. 10(17): e36624
    A novel prognostic model based on pyroptosis signature in AML.
    Huifang Zhang, Hongkai Zhu, Yue Sheng, Zhao Cheng, Hongling Peng.
      Acute myeloid leukemia (AML), a highly heterogeneous myeloid malignancy, remains a challenge in terms of proper risk stratification. In this study, we developed a novel pyroptosis prognostic model based on pyroptosis-related gene pairs, which exhibited excellent prognostic performance across multiple cohorts (N = 1506) and accurately predicted both adult and pediatric AML prognosis. Additionally, we integrated the pyroptosis risk model with other clinical risk factors to construct a highly operational nomogram. Moreover, our findings indicate a significant correlation between elevated pyroptosis risk scores and increased stemness of AML. Using CIBERSORT immune analysis, we found a decreased proportion of resting NK cells and activated mast cells in the high-risk group. Through analyzing the correlation between chemotherapy drug response sensitivity and risk scores, we found that AZD1332 and BPD-0008900 were extremely sensitive in the high-risk group.
    Keywords:  Acute myeloid leukemia; Bioinformatics; Gene pairs; Prognostic model; Pyroptosis
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e36624
  16. Nat Commun. 2024 Sep 09. 15(1): 7886
    Cytosolic FKBPL and ER-resident CKAP4 co-regulates ER-phagy and protein secretion.
    Cathena Meiling Li, Jaemin Kang, Jongyeon Baek, Youbin Kim, Heemin Park, Yong-Keun Jung.
      Endoplasmic reticulum quality control is crucial for maintaining cellular homeostasis and adapting to stress conditions. Although several ER-phagy receptors have been identified, the collaboration between cytosolic and ER-resident factors in ER fragmentation and ER-phagy regulation remains unclear. Here, we perform a phenotype-based gain-of-function screen and identify a cytosolic protein, FKBPL, functioning as an ER-phagy regulator. Overexpression of FKBPL triggers ER fragmentation and ER-phagy. FKBPL has multiple protein binding domains, can self-associate and might act as a scaffold connecting CKAP4 and LC3/GABARAPs. CKAP4 serves as a bridge between FKBPL and ER-phagy cargo. ER-phagy-inducing conditions increase FKBPL-CKAP4 interaction followed by FKBPL oligomerization at the ER, leading to ER-phagy. In addition, FKBPL-CKAP4 deficiency leads to Golgi disassembly and lysosome impairment, and an increase in ER-derived secretory vesicles and enhances cytosolic protein secretion via microvesicle shedding. Taken together, FKBPL with the aid of CKAP4 induces ER fragmentation and ER-phagy, and FKBPL-CKAP4 deficiency facilitates protein secretion.
    DOI:  https://doi.org/10.1038/s41467-024-52188-7
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