bims-lycede 2024-08-04 papers

Life Sci Alliance. 2024 Oct;pii: e202402677. [Epub ahead of print]7(10):

Golgi pH homeostasis stabilizes the lysosomal membrane through N-glycosylation of membrane proteins.

Yu-Shin Sou, Junji Yamaguchi, Keisuke Masuda, Yasuo Uchiyama, Yusuke Maeda, Masato Koike.

Protein glycosylation plays a vital role in various cellular functions, many of which occur within the Golgi apparatus. The Golgi pH regulator (GPHR) is essential for the proper functioning of the Golgi apparatus. The lysosomal membrane contains highly glycosylated membrane proteins in abundance. This study investigated the role of the Golgi luminal pH in N-glycosylation of lysosomal membrane proteins and the effect of this protein modification on membrane stability using Gphr-deficient MEFs. We showed that Gphr deficiency causes an imbalance in the Golgi luminal pH, resulting in abnormal protein N-glycosylation, indicated by a reduction in sialylated glycans and markedly reduced molecular weight of glycoproteins. Further experiments using FRAP and PLA revealed that Gphr deficiency prevented the trafficking dynamics and proximity condition of glycosyltransferases in the Golgi apparatus. In addition, incomplete N-glycosylation of lysosomal membrane proteins affected lysosomal membrane stability, as demonstrated by the increased susceptibility to lysosomal damage. Thus, this study highlights the critical role of Golgi pH regulation in controlling protein glycosylation and the impact of Golgi dysfunction on lysosomal membrane stability.

DOI: https://doi.org/10.26508/lsa.202402677

Anim Cells Syst (Seoul). 2024 ;28(1): 367-380

ESCRT-III: a versatile membrane remodeling machinery and its implications in cellular processes and diseases.

Jisoo Park, Jongyoon Kim, Hyungsun Park, Taewan Kim, Seongju Lee.

The endosomal sorting complexes required for transport (ESCRT) machinery is an evolutionarily conserved cytosolic protein complex that plays a crucial role in membrane remodeling and scission events across eukaryotes. Initially discovered for its function in multivesicular body (MVB) formation, the ESCRT complex has since been implicated in a wide range of membrane-associated processes, including endocytosis, exocytosis, cytokinesis, and autophagy. Recent advances have elucidated the ESCRT assembly pathway and highlighted the distinct functions of the various ESCRT complexes and their associated partners. Among the ESCRT complexes, ESCRT-III stands out as a critical player in membrane remodeling, with its subunits assembled into higher-order multimers capable of bending and severing membranes. This review focuses on the ESCRT-III complex, exploring its diverse functions in cellular processes beyond MVB biogenesis. We delve into the molecular mechanisms underlying ESCRT-III-mediated membrane remodeling and highlight its emerging roles in processes such as viral budding, autophagosome closure, and cytokinetic abscission. We also discuss the implications of ESCRT-III dysregulation in neurodegenerative diseases. The versatile membrane remodeling capabilities of ESCRT-III across diverse cellular processes underscore its importance in maintaining proper cellular function. Furthermore, we highlight the promising potential of ESCRT-III as a therapeutic target for neurodegenerative diseases, offering insights into the treatments of the diseases and the technical applications in related research fields.

Keywords: Autophagy; ESCRT-III; MVB; membrane remodeling; neurodegenerative disease

DOI: https://doi.org/10.1080/19768354.2024.2380294

Acta Pharmacol Sin. 2024 Aug 01.

Natural autophagy modulators in non-communicable diseases: from autophagy mechanisms to therapeutic potential.

Ting-Ting Xu, Ying-Yi Deng, Xi-Yong Yu, Min Li, Yuan-Yuan Fu.

Non-communicable diseases (NCDs) are defined as a kind of diseases closely related to bad behaviors and lifestyles, e.g., cardiovascular diseases, cancer, and diabetes. Driven by population growth and aging, NCDs have become the biggest disease burden in the world, and it is urgent to prevent and control these chronic diseases. Autophagy is an evolutionarily conserved process that degrade cellular senescent or malfunctioning organelles in lysosomes. Mounting evidence has demonstrated a major role of autophagy in the pathogenesis of cardiovascular diseases, cancer, and other major human diseases, suggesting that autophagy could be a candidate therapeutic target for NCDs. Natural products/phytochemicals are important resources for drugs against a wide variety of diseases. Recently, compounds from natural plants, such as resveratrol, curcumin, and ursolic acid, have been recognized as promising autophagy modulators. In this review, we address recent advances and the current status of the development of natural autophagy modulators in NCDs and provide an update of the latest in vitro and in vivo experiments that pave the way to clinical studies. Specifically, we focus on the relationship between natural autophagy modulators and NCDs, with an intent to identify natural autophagy modulators with therapeutic potential.

Keywords: autophagy modulators; cancer; cardiovascular diseases; diabetes; natural products; non-communicable diseases

DOI: https://doi.org/10.1038/s41401-024-01356-y

Bioorg Chem. 2024 Jul 27. pii: S0045-2068(24)00585-6. [Epub ahead of print]151 107680

Transcriptomic analysis of MCF7 breast cancer cells treated with MGBs reveals a profound inhibition of estrogen receptor genes.

Hasan Y Alniss, Maha M Saber-Ayad, Wafaa S Ramadan, Poorna Manasa Bhamidimarri, Yousef A Msallam, Hadeel M Al-Jubeh, Anil Ravi, Varsha Menon, Rifat Hamoudi, Raafat El-Awady.

Breast cancer poses a significant health risk worldwide. However, the effectiveness of current chemotherapy is limited due to increasing drug resistance and side effects, making it crucial to develop new compounds with novel mechanism of action that can surpass these limitations. As a consequence of their reversible and targeted mechanism, DNA minor groove binders (MGBs) are considered as a relatively safer and more effective alternative. In this study, transcriptomic analysis was conducted to reveal the dysregulated genes and signaling pathways in MCF7 cancer cells following treatment with novel MGB ligands to gain insights into the mechanism of action of MGBs at the molecular level. The transcriptomic results were validated using real-time PCR. The findings of this study indicate that the investigated MGBs primarily inhibit the genes associated with the estrogen receptor. Remarkably, ligand 5 showed downregulation of 34 out of the 35 genes regulated by estrogen receptor, highlighting its potential as a promising candidate for breast cancer therapy.

Keywords: Breast Cancer; Estrogen receptor (ER); MCF7; Minor Groove Binder (MGB); Transcriptomic analysis

DOI: https://doi.org/10.1016/j.bioorg.2024.107680

iScience. 2024 Aug 16. 27(8): 110432

Targeted dephosphorylation of TFEB promotes its nuclear translocation.

Jin-Feng Zhao, Natalia Shpiro, Gajanan Sathe, Abigail Brewer, Thomas J Macartney, Nicola T Wood, Florentina Negoita, Kei Sakamoto, Gopal P Sapkota.

Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.

Keywords: Health sciences; Medical specialty; Medicine; Precision medicine

DOI: https://doi.org/10.1016/j.isci.2024.110432