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Abstract: FR-PO241

Cardiotrophin-Like Cytokine Factor 1 (CLCF1), Proposed Permeability Factor in FSGS, Attenuates Autophagy and Maintains p-STAT3 (Ser727) via Upregulation of Mammalian Target of Rapamycin (mTOR)

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation


  • Sharma, Mukut, KCVA Medical Center, Kansas City, Missouri, United States
  • Zhou, Jianping, KCVA Medical Center, Kansas City, Missouri, United States
  • Chen, Maohui, KCVA Medical Center, Kansas City, Missouri, United States
  • De, Alok, MBRF, Kansas City VAMC, Kansas City, Missouri, United States
  • Sharma, Ram, Kansas City VA Medical Center, Kansas City, Missouri, United States
  • Srivastava, Tarak, Childrens's Mercy Hospital, Kansas City, Missouri, United States
  • McCarthy, Ellen T., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Gauchat, Jean-francois, University of Montreal, Montreal, Alberta, Canada
  • Savin, Virginia J., KC VA Medical Center, Kansas City, Alabama, United States

Autophagy, a critical mechanism for survival of podocytes, is downregulated in FSGS. We showed that an affinity purified fraction (Gal-FS) of plasma of patients with recurrent FSGS (recFSGS) or CLCF1, a cytokine of the IL-6 family that we identified in Gal-FS, increases glomerular albumin permeability (Palb) and upregulates JAK/STAT signaling. These effects are blocked by the heterodimer cytokine receptor-like factor1 (CRLF1)-CLCF1 (Trans Res 2015;166:384-398). Mechanism of CLCF1-induced damage to podocytes is not known. We hypothesized that monomeric CLCF1 and FSGS plasma/serum attenuate autophagy through upregulation of mTOR.


Galactose affinity chromatography was used to obtain Gal-FS containing CLCF1 detected by proteomic analysis using LC-MS/MS. Immortalized mouse podocytes were incubated (to 48h) with Gal-FS (<5µg protein), monomeric recombinant human CLCF1 (CLCF1,100 ng/mL), heterodimer CRLF1-CLCF1 (100-400ng/mL), Rapamycin (RAPA, ≥0.1µM) and activators/inhibitors at indicated concentrations. Cell morphology and expression of mTOR, STAT3 and autophagy molecules LC3s and other ATGs were determined using light/fluorescence microscopy and Western blot analysis.


Gal-FS or CLCF1 increased phospho-mTOR (15min+) and total mTOR in a dose and time-dependent manner that was blocked by CRLF-CLCF1. CLCF1 blocked the RAPA-induced decrease in total mTOR (P<.05) and phospho-mTOR levels (P<.001). Replenishing CLCF1 at 24h further increased mTOR levels at 48h (P<.005). CLCF1 w/wo RAPA, downregulated MAP1 LC3B (ATG8), a marker of autophagy-related processes (P<.005). ATGs 3, 5, 6 (beclin) and 7 were also modulated by CLCF1. Further work showed that CLCF1 blocked (P<.002) the RAPA-induced downregulation (P<.001) of p-STAT3(Ser727 but not Tyr705) suggesting specific regulation of STAT3 by mTOR kinase activity. Ongoing work indicates that CLCF1 also alters the phosphorylation of ERK and AKT- key cellular regulators that interact with mTOR.


Monomeric CLCF1 changes cellular homeostasis through attenuation of autophagy process via upregulation of mTOR which, in turn, also modulates STAT3 function. This may contribute to long-term podocyte loss and glomerular damage in recFSGS.


  • NIDDK Support