Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Ubiquitin-Proteasome Pathway and p62/SQSTM1 are Involved in The Rapid Degradation and Aggregation Mechanisms of CHK1 Mutant-Derived Toxic AGEs Formed by Glyceraldehyde

Version 1 : Received: 25 May 2023 / Approved: 26 May 2023 / Online: 26 May 2023 (11:53:35 CEST)

A peer-reviewed article of this Preprint also exists.

Takeda, K.; Sakai-Sakasai, A.; Kajinami, K.; Takeuchi, M. A Novel Approach: Investigating the Intracellular Clearance Mechanism of Glyceraldehyde-Derived Advanced Glycation End-Products Using the Artificial Checkpoint Kinase 1 d270KD Mutant as a Substrate Model. Cells 2023, 12, 2838. https://doi.org/10.3390/cells12242838 Takeda, K.; Sakai-Sakasai, A.; Kajinami, K.; Takeuchi, M. A Novel Approach: Investigating the Intracellular Clearance Mechanism of Glyceraldehyde-Derived Advanced Glycation End-Products Using the Artificial Checkpoint Kinase 1 d270KD Mutant as a Substrate Model. Cells 2023, 12, 2838. https://doi.org/10.3390/cells12242838

Abstract

Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in the non-enzymatic reaction with intracellular proteins, are highly cytotoxic and have been implicated in the pathogenesis of various diseases. However, the mechanisms underlying the degradation and removal of TAGE remain largely unknown. In the present study, we identified the checkpoint kinase-1 (CHK1) mutant, d270KD, which was rapidly degraded intracellularly by GA, and showed that its degradation was mainly mediated by the ubiquitin-proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of TAGE. The knockdown of p62/SQSTM1 reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of TAGE aggregates. The present results suggest that the ubiquitin-proteasome pathway and p62 play a role in the degradation and aggregation of intracellular TAGE formed by GA. This study provides new insights into the mechanisms underlying TAGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with TAGE accumulation.

Keywords

advanced glycation end-products (AGEs); glyceraldehyde (GA); glyceraldehyde-derived AGEs; toxic-AGEs (TAGE); p62/SQSTM1

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

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