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KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity

Guokai Yan1,2,3, Xiuzhi Li1,2,3, Zilong Zheng1,2,3

  • 1State Key Laboratory of Agricultural Microbiology, College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.

Autophagy
|March 10, 2022
PubMed

Insights

Calnexin (CANX) regulates the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway in response to leucine availability. This study identifies CANX’s lysosomal translocation and crotonylation as key steps in MTORC1 signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Amino acids are critical regulators of the MTORC1 pathway.
  • The precise mechanisms linking amino acid availability to MTORC1 activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of calnexin (CANX) in leucine-mediated MTORC1 activation.
  • To identify novel regulators and mechanisms governing MTORC1 signaling in response to nutrient cues.

Main Methods:

  • Development of a cell-free system to mimic MTORC1 activation.
  • Investigated protein localization, interactions, and post-translational modifications using techniques like knockout studies and biochemical assays.

Main Results:

  • Identified calnexin (CANX) as a crucial regulator of leucine-stimulated MTORC1 signaling.
  • Demonstrated that CANX translocates to lysosomes upon leucine deprivation and is essential for MTORC1 regulation.
  • Uncovered that CANX interacts with lysosomal associated membrane protein 2 (LAMP2) and undergoes lysine crotonylation mediated by lysine acetyltransferase 7 (KAT7), both critical for its function.

Conclusions:

  • Calnexin (CANX) acts as a key sensor and regulator in the leucine-MTORC1 pathway.
  • Lysosomal translocation and lysine crotonylation of CANX are essential for nutrient-dependent MTORC1 signaling.
  • This research provides novel insights into the intricate regulatory network of MTORC1.
Keywords:
CANXKAT7LAMP2MTORC1leucinelysine crotonylationragulator

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