Triamterene induces autophagic degradation of lysosome by exacerbating lysosomal integrity

Na Yeon Park,Joon Bum Kim,Yong-Keun Jung,Ji Yeon Choi,Ha Jung Lee,Ji-Eun Bae,Heeyoun Bunch,Dong-Hyung Cho,Hyun Jun Park,Doo Sin Jo,Hong Bae Jeon,Yong Hwan Kim,Jeong Ho Chang

doi:10.1007/s12272-021-01335-5

Abstract

The maintenance of lysosomal integrity is essential for lysosome function and cell fate. Damaged lysosomes are degraded by lysosomal autophagy, lysophagy. The mechanism underlying lysophagy remains largely unknown; this study aimed to contribute to the understanding of this topic. A cell-based screening system was used to identify novel lysophagy modulators. Triamterene (6-phenylpteridine-2,4,7-triamine) was identified as one of the most potent lysophagy inducers from the screening process. We found that triamterene causes lysosomal rupture without affecting other cellular organelles and increases autophagy flux in HepG2 cells. Damaged lysosomes in triamterene-treated cells were removed by autophagy-mediated pathway, which was inhibited by depletion of the autophagy regulator, ATG5 or SQSTM1. In addition, treatment of triamterene decreased the integrity of lysosome and cell viability, which were rescued by removing the triamterene treatment in HepG2 cells. Hence, our data suggest that triamterene is a novel lysophagy inducer through the disruption of lysosomal integrity.

Highlights

Lysosomes, single membrane-bound organelles, are responsible for various cellular functions, including the degradation of extra- or intracellular materials, nutrient sensing and recycling, cholesterol homeostasis, and cell death (Settembre et al 2013)
The results showed that ER, Golgi, mitochondria, and peroxisome were not notably changed by treatment with triamterene in HepG2 cells, while some swelling was observed in lysosomes (Fig. 1 C)
Various lysosomotropic agents promote the enlargement of the lysosome and ultimate lysosomal membrane permeabilization (LMP), which triggers cellular stress responses (Wang et al 2018a, b)

Summary

Introduction

Single membrane-bound organelles, are responsible for various cellular functions, including the degradation of extra- or intracellular materials, nutrient sensing and recycling, cholesterol homeostasis, and cell death (Settembre et al 2013). As the main organelles of degradation, lysosomes contain more than 60 degradative enzymes, such as proteases, lipases, nucleases, and other hydrolases, which are optimally activated in acidic pH conditions (Perera and Zoncu 2016). According to this notion, disruption of the lysosome results in increased cytosolic acidity, and leakage of these enzymes into the cytoplasm can trigger cell death (Kroemer and Jäättelä 2005; Papadopoulos and Meyer 2017).

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