Research Paper Volume 16, Issue 13 pp 10749—10764
Cathepsin L induces cellular senescence by upregulating CUX1 and p16INK4a
- 1 Department of Cardiology, Third Xiangya Hospital, Central South University, Changsha, China
- 2 Aging Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 3 International Center for Aging and Cancer Hainan Medical University, Hainan, China
- 4 Tsinghua Medicine, Tsinghua University, Peking, China
- 5 Department of Medicine, Division of Cardiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- 6 Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Received: September 19, 2023 Accepted: April 18, 2024 Published: June 18, 2024
https://doi.org/10.18632/aging.205955How to Cite
Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Cathepsin L (CTSL) has been implicated in aging and age-related diseases, such as cardiovascular diseases, specifically atherosclerosis. However, the underlying mechanism(s) is not well documented. Recently, we demonstrated a role of CUT-like homeobox 1 (CUX1) in regulating the p16INK4a-dependent cellular senescence in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via its binding to an atherosclerosis-associated functional SNP (fSNP) rs1537371 on the CDKN2A/B locus. In this study, to determine if CTSL, which was reported to proteolytically activate CUX1, regulates cellular senescence via CUX1, we measured the expression of CTSL, together with CUX1 and p16INK4a, in human ECs and VSMCs undergoing senescence. We discovered that CUX1 is not a substrate that is cleaved by CTSL. Instead, CTSL is an upstream regulator that activates CUX1 transcription indirectly in a process that requires the proteolytic activity of CTSL. Our findings suggest that there is a transcription factor in between CTSL and CUX1, and cleavage of this factor by CTSL can activate CUX1 transcription, inducing endothelial senescence. Thus, our findings provide new insights into the signal transduction pathway that leads to atherosclerosis-associated cellular senescence.