bims-raghud 2024-12-22 papers

Issue of 2024–12–22
four papers selected by
Irene Sambri, TIGEM

Immunity. 2024 Dec 12. pii: S1074-7613(24)00532-6. [Epub ahead of print]

The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance.

Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan.

Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.

Keywords: STING; TFEB; cGAS; innate immunity; lysosome

DOI: https://doi.org/10.1016/j.immuni.2024.11.017

Autophagy. 2024 Dec 15. 1-21

AMPK protects proximal tubular epithelial cells from lysosomal dysfunction and dedifferentiation induced by lipotoxicity.

Louise Pierre, Florian Juszczak, Valentine Delmotte, Morgane Decarnoncle, Benjamin Ledoux, Laurent Bultot, Luc Bertrand, Marielle Boonen, Patricia Renard, Thierry Arnould, Anne-Emilie Declèves.

Renal proximal tubules are a primary site of injury in metabolic diseases. In obese patients and animal models, proximal tubular epithelial cells (PTECs) display dysregulated lipid metabolism, organelle dysfunctions, and oxidative stress that contribute to interstitial inflammation, fibrosis and ultimately end-stage renal failure. Our research group previously pointed out AMP-activated protein kinase (AMPK) decline as a driver of obesity-induced renal disease. Because PTECs display high macroautophagic/autophagic activity and rely heavily on their endo-lysosomal system, we investigated the effect of lipid stress on autophagic flux and lysosomes in these cells. Using a model of highly differentiated primary PTECs challenged with palmitate, our data placed lysosomes at the cornerstone of the lipotoxic phenotype. As soon as 6 h after palmitate exposure, cells displayed impaired lysosomal acidification subsequently leading to autophagosome accumulation and activation of lysosomal biogenesis. We also showed the inability of lysosomal quality control to restore acidic pH which finally drove PTECs dedifferentiation. When palmitate-induced AMPK activity decline was prevented by AMPK activators, lysosomal acidification and the differentiation profile of PTECs were preserved. Our work provided key insights on the importance of lysosomes in PTECs homeostasis and lipotoxicity and demonstrated the potential of AMPK in protecting the organelle from lipid stress.Abbreviation: ACAC: acetyl-CoA carboxylase; ACTB: actin beta; AICAR: 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK: AMP-activated protein kinase; APQ1: aquaporin 1 (Colton blood group); BSA: bovine serum albumin; CDH16: cadherin 16; CKD: chronic kidney disease; CTSB: cathepsin B; CTSD: cathepsin D; EPB41L5: erythrocyte membrane protein band 4.1 like 5; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EMT: epithelial-to-mesenchymal transition; FA: fatty acid; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; GUSB: glucuronidase beta; HEXB: hexosaminidase subunit beta; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; LMP: lysosomal membrane permeabilization; LRP2: LDL receptor related protein 2; LSD: lysosomal storage disorder; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TRP cation channel 1; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MmPTECs: Mus musculus (mouse) proximal tubular epithelial cells; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleate; PA: palmitate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PTs: proximal tubules; PTECs: proximal tubular epithelial cells; PRKAA: protein kinase AMP-activated catalytic subunit alpha; RFP: red fluorescent protein; RPS6KB: ribosomal protein S6 kinase B; SLC5A2: solute carrier family 5 member 2; SOX9: SRY-box transcription factor 9; SQSTM1: sequestosome 1; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin.

Keywords: AMPK; Autophagy; chronic kidney disease; lipid accumulation; obesity; proximal tubules

DOI: https://doi.org/10.1080/15548627.2024.2435238

JCI Insight. 2024 Dec 19. pii: e184451. [Epub ahead of print]

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy-lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly CKD patients remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied with mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance reflected by the accumulation of mitochondria-lysosome-related organelles, which depends on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.

Keywords: Chronic kidney disease; Fatty acid oxidation; Metabolism; Mitochondria; Nephrology

DOI: https://doi.org/10.1172/jci.insight.184451

Kidney Int. 2024 Dec 15. pii: S0085-2538(24)00872-X. [Epub ahead of print]

Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease.

Erika Folestad, Annika Mehlem, Frank Chenfei Ning, Timo Oosterveld, Isolde Palombo, Jaskaran Singh, Hannes Olauson, Anna Witasp, Anders Thorell, Peter Stenvinkel, Kerstin Ebefors, Jenny Nyström, Ulf Eriksson, Annelie Falkevall.

A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84 %) and Type 1 diabetes (16 %), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyzes in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.

Keywords: Diabetic kidney disease; Vascular endothelial growth factor B; kidney lipotoxicity; lipolysis; tissue cross talk; white adipose tissue

DOI: https://doi.org/10.1016/j.kint.2024.11.026