bims-raghud 2026-03-22 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–03–22
twelve papers selected by
Irene Sambri, TIGEM

ZDHHC9 palmitoylates LAMTOR1 to promote renal cell carcinoma malignant progression.
Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
The Cyclin C-CDK8/19 Mediator kinase module controls PRCC-TFE3 driven senescence in renal epithelium and tumorigenesis in TFE3-RCC.
Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
PE_PGRS23 promotes intracellular survival of Mycobacterium tuberculosis by competitively regulating autophagy gene expression through TFEB and USF2.
MFF budding from mitochondria regulates melanosome size and maturation.
Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
Regulator of Calcineurin 1 Aggravates Tubular Epithelial Cell Injury in Diabetic Mice Through Promoting Liver Kinase B1 Ubiquitination.
Advances in targeting myocardial fibrosis: integrating mechanisms and therapeutics.
Inflammatory signalling in diabetic cardiomyopathy: molecular mechanisms and potential therapeutic strategies.
HIF-1α Drives Cellular Senescence Via Autophagy Activation to Promote AKI-to-CKD Transition.

Cell Death Dis. 2026 Mar 19.

ZDHHC9 palmitoylates LAMTOR1 to promote renal cell carcinoma malignant progression.

Bo Liu, Tao Hou, Xizhi Liu, Lu Liu, Zhiqiang Ma, Yujiao Zhang.

The lysosomal regulator complex member LAMTOR1 serves as a crucial pivot that recruits the mechanistic target of rapamycin complex 1 (mTORC1) to the lysosomal surface, thereby influencing biological processes such as cell growth and cancer progression. In renal cell carcinoma (RCC), existing studies reveal that mTORC1 signaling contributes to cancer progression. However, the precise regulatory mechanisms underlying mTOR signaling in RCC remain unclear and warrant further investigation. Here, we demonstrate that the palmitoylation enzyme Zinc Finger DHHC-Type Containing 9 (ZDHHC9) activates the mTOR signaling pathway, thereby accelerating cancer progression and highlighting its potential role in RCC. In our study, we identified that ZDHHC9 specifically palmitoylates LAMTOR1 at its Cys3/4 residues, enhancing the recruitment of mTORC1 and subsequently activating the mTOR signaling cascade. Collectively, our findings provide novel insights into the pathogenesis of RCC and establish ZDHHC9 as a key mediator of RCC progression through the palmitoylation of LAMTOR1, which may serve as a promising target for the diagnosis and treatment of this malignancy.

DOI: https://doi.org/10.1038/s41419-026-08558-8
Nat Metab. 2026 Mar 18.

Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.

Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.

Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.

DOI: https://doi.org/10.1038/s42255-026-01484-1
Neoplasia. 2026 Mar 16. pii: S1476-5586(26)00025-4. [Epub ahead of print]75 101296

The Cyclin C-CDK8/19 Mediator kinase module controls PRCC-TFE3 driven senescence in renal epithelium and tumorigenesis in TFE3-RCC.

Shoichiro Kuroda, Shintaro Funasaki, Hidekazu Nishizawa, Laura S Schmidt, Ryoma Kurahashi, Takaaki Ito, Yuichiro Arima, Miwa Tanaka, Atsuya Kitada, Amy M James, Hisashi Hasumi, Ryosuke Jikuya, Kazuhide Makiyama, Daisuke Kurotaki, Takashi Minami, Simone Difilippantonio, W Marston Linehan, Yuichi Oike, Tomohiro Sawa, Yasuhito Tanaka, Toshio Suda, Ryuji Yokokawa, Takuro Nakamura, Masaya Baba, Tomomi Kamba.

  TFE3-rearranged renal cell carcinoma (TFE3-RCC) is an aggressive kidney cancer driven by oncogenic TFE3 fusion transcription factors, yet the molecular machinery that enables these fusions to reprogram transcription and drive tumor growth remains poorly defined. Here, we identify the Cyclin C-CDK8/19 Mediator kinase module as an essential co-regulator of TFE3 fusion driven transcriptional programs and tumorigenesis. Inducible expression of PRCC-TFE3 in HK-2 cells, immortalized from normal renal epithelial cells, triggered a robust oncogene-induced senescence (OIS) phenotype. Using OIS as a functional readout, we performed a genome-wide CRISPR/Cas9 loss-of-function screen and identified CCNC, encoding Cyclin C, as an essential gene required for PRCC-TFE3 activity. Genetic disruption of CCNC or pharmacologic inhibition of CDK8/19 abrogated PRCC-TFE3 induced OIS, establishing the Mediator kinase module as a critical cofactor for PRCC-TFE3 dependent transcription. Mechanistically, PRCC-TFE3 promoted nuclear accumulation of Cyclin C and their co-occupancy at genomic regions bound and transcriptionally activated by PRCC-TFE3. RNA sequencing revealed that PRCC-TFE3 induced transcriptional programs, including lysosomal, TFEB-associated, and metabolic pathways, were broadly suppressed by CDK8/19 inhibition. Importantly, while PRCC-TFE3 and Cyclin C-CDK8/19 drive OIS in non-cancerous renal epithelial cells, this same transcriptional axis exerts a context dependent pro-tumorigenic function in TFE3-RCC. In xenografts established from patient derived TFE3-RCC cell lines, genetic deletion of CCNC suppressed tumor growth, whereas in an orthotopic syngeneic TFE3-RCC mouse model, pharmacologic CDK8/19 inhibition significantly reduced tumor progression. These findings define the Mediator kinase module as a mechanistic and therapeutic vulnerability in PRCC-TFE3 driven TFE3-RCC, providing a rationale for mechanism based targeted therapy.

Keywords:  CCNC; CDK8/19; CRISPR/Cas9 genome-wide screen; Cyclin C; Mediator complex; TFE3 fusion; TFE3-rearranged renal cell carcinoma

DOI:  https://doi.org/10.1016/j.neo.2026.101296
Nat Commun. 2026 03 14. pii: 2487. [Epub ahead of print]17(1):

Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.

Valentin Duhay, Miaomiao Tian, Klaudia Kosieradzka, Michael Ebner, Wen-Ting Lo, Michael Krauss, Henner-Linus Sprengel, Matthias Voss, Mara Riechmann, Jeffrey N Savas, Michael Schwake, Volker Haucke, Markus Damme.

Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.

DOI: https://doi.org/10.1038/s41467-026-70345-y
J Immunol. 2026 Mar 17. pii: vkag029. [Epub ahead of print]215(3):

PE_PGRS23 promotes intracellular survival of Mycobacterium tuberculosis by competitively regulating autophagy gene expression through TFEB and USF2.

Tingting Feng, Zhenjun Zhang, Hui Wang, Xinxin Zang, Jiajun Zhang, Yanyan Jiang, Yingying Cui, Yifan Duan, Ruonan Guo, Yunjie Gao, Chunwen Chen, Guanghui Dang, Siguo Liu.

  Autophagy serves as a crucial defense mechanism against Mycobacterium tuberculosis (Mtb) survival within infected macrophages. Transcription factor EB (TFEB) and upstream stimulatory factor 2 (USF2) belong to the bHLH-Zip family and regulate the transcription of autophagy-related genes, thereby modulating host-pathogen interactions. However, the mechanisms by which Mtb regulates these transcriptional regulatory factors to inhibit infection remain largely unexplored. This study demonstrated that PE_PGRS23 protein of Mtb impairs macrophage autophagy by inhibiting the transcription of the autophagy gene, thereby enhancing Mtb intracellular survival. Importantly, PE_PGRS23 facilitates the nuclear translocation of TFEB through PI3K-AKT-mTOR-mediated dephosphorylation. Concurrently, PE_PGRS23 promotes the nuclear translocation of USF2, which competes with TFEB for binding to the MAPLC3 promoter, ultimately suppressing MAPLC3 transcription and inhibiting autophagy. Furthermore, murine infection models demonstrated that PE_PGRS23 enhances Mtb survival and exacerbates Mtb-induced lung tissue damage. These findings underscore the critical role of the Mtb PE_PGRS23 protein in inhibiting autophagy by competitively binding of TFEB and USF2 at the MAPLC3 promoter. This mechanism facilitates the intracellular persistence of Mtb, providing theoretical insights into how the pathogen evades innate immune responses.

Keywords:   Mycobacterium tuberculosis ; Autophagy; PE_PGRS23; TFEB; USF2

DOI:  https://doi.org/10.1093/jimmun/vkag029
Nat Commun. 2026 Mar 14.

MFF budding from mitochondria regulates melanosome size and maturation.

Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.

Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.

DOI: https://doi.org/10.1038/s41467-026-70572-3
J Diabetes Res. 2026 ;2026(1): e1498605

Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.

Tianlei Chen, Min Yang.

  Diabetic nephropathy (DN), a predominant cause of end-stage renal disease (ESRD), is primarily driven bfigolic disturbances and mitochondrial dysfunction. Apolipoprotein M (ApoM), a protein associated with high-density lipoprotein (HDL), is notably downregulated in DN and is correlated with a decline in renal function. Recent studies have identified a protective bidirectional axis between ApoM and mitophagy, the selective autophagy of mitochondria. ApoM, chiefly through its role as a carrier for sphingosine-1-phosphate (S1P), enhances mitophagy by activating the silent information regulator 1 (SIRT1) and parkin induced kinase 1 (PINK1)/Parkin pathways, thereby improving mitochondrial quality control. Conversely, mitophagy facilitates ApoM synthesis by supplying sufficient adenosine triphosphate (ATP) for its production and the assembly of HDL. In the context of DN, hyperglycemia disrupts this reciprocal relationship, leading to a detrimental cycle of impaired mitophagy and reduced ApoM, which exacerbates renal injury. Targeting the ApoM-mitophagy axis through ApoM enhancement or mitophagy activation emerges as a promising therapeutic approach for personalized renal protection in DN. This review synthesizes the mechanistic interplay between lipid metabolism and mitochondrial quality control, emphasizing its translational potential and the necessity for further investigation.

Keywords:  apolipoprotein m; diabetic nephropathy; lipid metabolism; mitophagy; sphingosine-1-phosphate

DOI:  https://doi.org/10.1155/jdr/1498605
EMBO J. 2026 Mar 20.

Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.

Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.

  Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.

Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation

DOI:  https://doi.org/10.1038/s44318-026-00741-z
FASEB J. 2026 Mar 31. 40(6): e71712

Regulator of Calcineurin 1 Aggravates Tubular Epithelial Cell Injury in Diabetic Mice Through Promoting Liver Kinase B1 Ubiquitination.

Jing-Jie Xiao, Ying Li, LiJiao Yang, Hong-Min Chen, Jun-Wei Hu, Bin-Bin Hu, QianYu Lu, Huanhuan Cai, Di Fan, XiaoYan Wu, Zhibing Lu, Bai-Fang Zhang.

  Renal tubular injury is closely related to the occurrence and development of diabetic kidney disease (DKD). Regulator of calcineurin 1 (RCAN1) is an endogenous regulatory factor of the phosphatase calcineurin and plays an important role in cell differentiation and the regulation of mitochondrial function. However, the underlying mechanism of RCAN1 in renal tubular injury in DKD remains unclear. Here, we found that RCAN1 expression is predominantly upregulated in renal tubular epithelial cells (RTECs) of patients with DKD and mice with streptozotocin-induced diabetic kidney injury. RCAN1 overexpression in RTECs significantly exacerbates mitochondrial damage and interstitial fibrosis in diabetic mice. Furthermore, RCAN1 overexpression reduces AMP-activated protein kinase (AMPK) phosphorylation, activates the mTOR/PRAS40/S6K signaling pathway, and promotes lipid deposition. Co-immunoprecipitation and mass spectrometry analysis reveal an interaction between RCAN1 and AMPK upstream kinase liver kinase B1 (LKB1). Mechanistically, RCAN1 directly binds to a deubiquitinase BRCA1-associated protein 1 (BAP1) through the N-terminal residues 1-29. The binding reduces the stability of the LKB1-MO25-STRAD complex in the cytoplasm by inhibiting BAP1-mediated deubiquitination of these proteins. Our findings provide for the first time the role of RCAN1 in regulating protein ubiquitination modification. In conclusion, RCAN1 promotes tubular damage by disrupting the LKB1/AMPK pathway in RTECs under HG conditions. RCAN1 may act as a potential therapeutic target for preventing DKD progression.

Keywords:  diabetic kidney disease (DKD); liver kinase 1 (LKB1); mitochondrial homeostasis; regulator of calcineurin 1 (RCAN1); ubiquitination

DOI:  https://doi.org/10.1096/fj.202503456RR
Front Cardiovasc Med. 2026 ;13 1769016

Advances in targeting myocardial fibrosis: integrating mechanisms and therapeutics.

Zihui Xu, Yuyan Zhao.

  Myocardial fibrosis (MF) is a maladaptive pathological response of the heart to chronic injury. Accumulating evidence indicates that MF plays a central role in the development and progression of hypertensive heart disease, ischemic cardiomyopathy, diabetic cardiomyopathy, and heart failure, and is closely associated with an increased risk of arrhythmias and sudden cardiac death. In recent years, advances in experimental and analytical approaches have improved our understanding of the molecular mechanisms underlying MF and informed the development of potential therapeutic strategies. However, many existing pharmacological interventions exhibit limited target specificity, uncertain long-term efficacy, and incompletely defined mechanisms of action in humans. In this review, we summarize the major molecular pathways involved in myocardial fibrosis and discuss current and emerging therapeutic approaches, incorporating mechanistic insights from recent single-cell and spatial transcriptomic studies to better contextualize fibrotic signaling heterogeneity and translational challenges.

Keywords:  drug development; fibroblast activation; heart failure; myocardial fibrosis; therapeutic targets

DOI:  https://doi.org/10.3389/fcvm.2026.1769016
Nat Rev Cardiol. 2026 Mar 20.

Inflammatory signalling in diabetic cardiomyopathy: molecular mechanisms and potential therapeutic strategies.

Miles J De Blasio, Rebecca H Ritchie.

Diabetes mellitus and the associated increased risk of cardiovascular disease is a major health-care issue worldwide. Diabetic cardiomyopathy, a complication of diabetes mellitus, is driven primarily by hyperglycaemia and hyperlipidaemia, which promote cardiac oxidative stress, mitochondrial dysfunction and pathological cardiac remodelling, leading to impaired cardiac function and eventual heart failure. Over the past 30 years, research on diabetic cardiomyopathy and other diabetes-associated cardiovascular diseases has focused on the role of chronic inflammation. Inflammation is a complex process involving pro-inflammatory cytokines, chemokines, activation of resident immune cells, and recruitment of immune cells to sites of injury, processes that are exacerbated in the setting of diabetes. Evidence now suggests that the inflammatory processes caused by persistent hyperglycaemia and hyperlipidaemia in diabetes contribute to the impairment of cardiac function. Importantly, no treatment options are available to reverse diabetic cardiomyopathy, with clinicians relying on strategies to delay or halt the progression of the disease. In this Review, we describe the inflammatory signalling pathways involved in diabetic cardiomyopathy and discuss strategies that can potentially be used to target these inflammatory pathways for the treatment of diabetic cardiomyopathy.

DOI: https://doi.org/10.1038/s41569-026-01274-y
Am J Nephrol. 2026 Mar 16. 1-31

HIF-1α Drives Cellular Senescence Via Autophagy Activation to Promote AKI-to-CKD Transition.

Manzhu Zhang, Lingxu Li, Xinyue Mao, Xiaoying Yun, Meiting Wu, Chang Wang, Bing Li.

INTRODUCTION: Ischemia and hypoxia are central drivers of acute kidney injury (AKI) and hypoxia-inducible factor (HIF) is a key regulator of cellular oxygen homeostasis. Our previous study showed that HIF-1α is protective during the early stage of AKI; however, its role in the transition from AKI to chronic kidney disease (CKD) remains unclear. Cellular senescence has been implicated in CKD progression and can be accelerated by hypoxia. Nevertheless, whether HIF-1α signaling mediates cellular senescence and promotes the AKI-to-CKD transition is poorly understood.
METHODS: Ischemia-reperfusion injury models of AKI with adaptive repair (AR) or maladaptive repair (MAR) were used to examine the dynamics of HIF-1α, cellular senescence and autophagy. In human renal proximal tubular epithelial cells (HK-2), a hypoxia/reoxygenation (H/R) injury model was used to evaluate the relationships among HIF-1α, autophagy and senescence. Finally, the association between HIF-1α levels and cellular senescence was assessed in renal biopsies from CKD patients.
RESULTS: The AR group exhibited rapid and sufficient HIF-1α expression, accompanied by acute senescence, with HIF-1α levels returning to baseline upon the completion of repair. In contrast, the MAR group showed delayed and sustained HIF-1α activation, driving chronic senescence and progressive fibrosis. The activation of autophagy was closely associated with the expression of HIF-1α in the AR and MAR groups. In vitro, silencing HIF-1α expression attenuated autophagy activity, senescence and fibrosis in HK-2 cells under H/R. However, HIF-1α overexpression had the opposite effect. The autophagy activator rapamycin reversed the inhibitory effects of HIF-1α knockdown, whereas the autophagy inhibitor bafilomycin A1 diminished the pro-senescent and pro-fibrotic effects of HIF-1α overexpression. Analysis of CKD patient biopsies confirmed elevated HIF-1α expression, which correlated with reduced eGFR, increased fibrosis, and enhanced cellular senescence.
CONCLUSION: Adequate HIF-1α activation during early AKI is associated with acute senescence and renal repair, whereas sustained HIF-1α drives chronic senescence via persistent autophagy activation, and may contribute to the AKI-to-CKD transition.

DOI: https://doi.org/10.1159/000551542