bims-raghud 2026-05-10 papers

Issue of 2026–05–10
four papers selected by
Irene Sambri, TIGEM

FEBS Lett. 2026 May 03.

pH-mediated activation of the lysosomal arginine sensor SLC38A9.

Cells rely on metabolic control; the mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, particularly amino acids. Lysosomes maintain amino acid homeostasis through recycling. SLC38A9, a lysosomal amino acid transporter, functions as a critical sensor in the mTORC1 pathway. Here, we investigate how pH regulates SLC38A9 activity. We show that arginine uptake is pH-dependent, with His544 residue serving as the pH sensor. Mutating His544 abolishes pH dependence without impairing overall transport, indicating His544 influences transport through protonation/deprotonation, instead of involving in the substrate binding. We propose a working model for pH-induced activation, through comparing two determined SLC38A9 structures at different pH. These findings reveal how local ionic shifts regulate lysosomal transporters and fine-tune SLC38A9 function to control mTORC1 signaling.

Keywords: SLC family; amino acid transport; mTOR complex; pH‐regulation; transceptor

DOI: https://doi.org/10.1002/1873-3468.70352

J Biol Chem. 2026 May 06. pii: S0021-9258(26)01983-6. [Epub ahead of print] 113111

Arylsulfatase L is a Golgi chondroitin sulfatase regulating skeletal development.

Marianna Maddaluno, Chiara De Leonibus, Eugenio Del Prete, Francesco Giuseppe Salierno, Daniela Intartaglia, Diego Carrella, Ivan Conte, Nicola Volpi, Carmine Settembre.

Sulfatases are a family of enzymes that hydrolyze sulfate esters from various substrates. Defects, in sulfatase activity, are associated with various human diseases due to the accumulation of sulfated substrates. Deficiency in ARSL, a Golgi sulfatase, is associated with X-linked recessive chondrodysplasia punctata (CDPX), a disorder characterized by defects in cartilage and bone development. However, until now, ARSL function has remained unknown. In this study, we demonstrate that ARSL promotes 4-O-desulfation of Chondroitin Sulfate (CS) during proteoglycan biosynthesis. Chondrocytes lacking ARSL exhibit hypersulfated CS and altered responses to TGF-β stimulation. Loss of function of ARSL orthologous in medaka fish (Ol-Arsd) results in hyper-4-O-sulfated CS, skeletal malformations, and craniofacial defects that partly resemble the human CDPX phenotype. Our findings uncover a previously unrecognized step in glycosaminoglycan (GAG) maturation-Golgi-based desulfation-and reveal a new layer of regulatory control in skeletal development.

Keywords: Chondroitin sulfate; Proteoglycan; Sulfatase; chondrodysplasia

DOI: https://doi.org/10.1016/j.jbc.2026.113111

Hum Pathol. 2026 May 06. pii: S0046-8177(26)00111-5. [Epub ahead of print] 106142

TSC2, Cathepsin K, and β-catenin as Immunohistochemical Markers for Lymphangioleiomyomatosis.

Abdullah Alfayez, Eric Belanger, Simon Cheung, Andrew Churg.

The diagnosis of lymphangioleiomyomatosis (LAM) can be straightforward when LAM cells are abundant, but may be difficult with subtle lesions mimicking emphysema or with lung architecture obscured by parenchymal collapse. A variety of markers have been proposed for immunohistochemical confirmation of LAM. The is increasing evidence from sequencing studies that tuberous sclerosis 2 (TSC2) is frequently mutated in sporadic LAM, and TSC2 expression/loss can now be demonstrated by immunohistochemistry but TSC2 immunohistochemistry has not been reported in LAM. Here we examined the immunohistochemical performance of TSC2, β-catenin, cathepsin K, and HMB-45 in 10 cases of pulmonary LAM (4 with florid lesions, 6 with only subtle lesions), 6 cases of pelvic nodal LAM, and two cases of micronodular pneumocyte hyperplasia (MNPH), the latter a common finding in TSC LAM cases. TSC2 loss was observed in all cases in both florid and subtle lesions, nodal LAM, and MNPH. HMB45 was focally positive in 5/10 pulmonary and 3/6 nodal cases. β-catenin was variably, but sometimes weakly, expressed in 6/6 nodal cases and 10/10 pulmonary case but was often difficult to interpret in subtle lesions. Cathepsin K showed consistent strong positivity in all pulmonary and nodal cases. We conclude that, in well inflated lung with obvious LAM lesions, β-catenin, cathepsin K, and TSC2 are easy to interpret. In subtle cases Cathepsin K staining is the easiest to interpret but TSC2 staining also picks up subtle cases and offers the advantage of confirming the genetic change that implies a potential response to mTOR inhibitor therapy.

Keywords: Cathepsin K; HMB45; Lymphangioleiomyomatosis; TSC2; β-catenin

DOI: https://doi.org/10.1016/j.humpath.2026.106142

Cell Commun Signal. 2026 May 06.

In vitro modeling of renal injury-induced cardiac effects using human iPSC-derived organoids.

Beatrice Gabbin, James Gallant, Fangchen Liu, Hailiang Mei, Berend J van Meer, Ton J Rabelink, Christine L Mummery, Jessica M Vanslambrouck, Cathelijne W van den Berg, Viviana Meraviglia, Milena Bellin.

The bidirectional communication between the heart and kidney is essential for physiological homeostasis, with injury in one organ often impairing the other. Although cardiorenal crosstalk is clinically relevant in conditions such as cardiorenal syndrome (CRS), the underlying molecular and cellular mechanisms remain poorly understood, and in vitro models are lacking. Here, we developed a co-culture system using human induced pluripotent stem cell (hiPSC)-derived kidney organoids (kOs) and cardiac microtissues (cMTs) to model the cardiorenal axis.kOs exposed to nephrotoxic compounds for 72 h displayed glomerular and tubular damage, reduced cell viability, and altered gene expression. When subsequently co-cultured with cMTs for 72 h, injured kOs induced secondary cardiac dysfunction characterized by reduced cell viability, impaired contractility, and endothelial cell loss. These findings demonstrate that kidney injury can elicit detrimental effects on cardiac tissues in vitro. This organoid-based platform offers a valuable tool for studying cardiorenal interactions and underlines the potential of multi-organ models for investigating mechanisms of interdependent organ dysfunction.

Keywords: Cardiac microtissues; Cardiorenal axis; Drug-induced toxicity; Inter-organ interaction; Kidney organoids

DOI: https://doi.org/10.1186/s12964-026-02902-3