Craig brooks
Faculty Member
Last active: 3/14/2019

Cyclin G1 and TASCC regulate kidney epithelial cell G-M arrest and fibrotic maladaptive repair.

Canaud G, Brooks CR, Kishi S, Taguchi K, Nishimura K, Magassa S, Scott A, Hsiao LL, Ichimura T, Terzi F, Yang L, Bonventre JV
Sci Transl Med. 2019 11 (476)

PMID: 30674655 · PMCID: PMC6527117 · DOI:10.1126/scitranslmed.aav4754

Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G-M arrest is induced in kidney injury and how G-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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