LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome-positive cancer cells

Nada Amer; Dina Hesham; Nouran Al-Shehaby; Hisham A Elshoky; May Amer; Sameh Magdeldin; Manar Mansour; Khaled Abou-Aisha; Shahenda El-Naggar

doi:10.1016/j.jbc.2024.107398

LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome-positive cancer cells

J Biol Chem. 2024 May 20;300(6):107398. doi: 10.1016/j.jbc.2024.107398. Online ahead of print.

Authors

Nada Amer¹, Dina Hesham¹, Nouran Al-Shehaby², Hisham A Elshoky², May Amer², Sameh Magdeldin³, Manar Mansour⁴, Khaled Abou-Aisha⁴, Shahenda El-Naggar⁵

Affiliations

¹ Tumor Biology Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt; Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt.
² Tumor Biology Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt.
³ Proteomics and Metabolomics Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt; Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.
⁴ Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt.
⁵ Tumor Biology Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt. Electronic address: shahenda.elnaggar@57357.org.

PMID: 38777145
DOI: 10.1016/j.jbc.2024.107398

Abstract

The unfolded protein response pathways (UPR), autophagy, and compartmentalization of misfolded proteins into inclusion bodies are critical components of the protein quality control network. Among inclusion bodies, aggresomes are particularly intriguing due to their association with cellular survival, drug resistance, and aggresive cancer behavior. Aggresomes are molecular condensates formed when collapsed vimentin cages encircle misfolded proteins before final removal by autophagy. Yet significant gaps persist in the mechanisms governing aggresome formation and elimination in cancer cells. Understanding these mechanisms is crucial, especially considering the involvement of LC3A, a member of the MAP1LC3 family, which plays a unique role in autophagy regulation and has been reported to be epigenetically silenced in many cancers. Herein, we utilized the tetracycline-inducible expression of LC3A to investigate its role in choroid plexus carcinoma cells, which inherently exhibit the presence of aggresomes. Live cell imaging was employed to demonstrate the effect of LC3A expression on aggresome-positive cells, while SILAC-based proteomics identified LC3A-induced protein and pathway alterations. Our findings demonstrated that extended expression of LC3A is associated with cellular senescence. However, the obstruction of lysosomal degradation in this context has a deleterious effect on cellular viability. In response to LC3A-induced autophagy, we observed significant alterations in mitochondrial morphology, reflected by mitochondrial dysfunction and increased ROS production. Furthermore, LC3A expression elicited the activation of the PERK-eIF2α-ATF4 axis of the UPR, underscoring a significant change in the protein quality control network. In conclusion, our results elucidate that LC3A-mediated autophagy alters the protein quality control network, exposing a vulnerability in aggresome-positive cancer cells.

Keywords: MAP1LC3A; aggresomes; autophagy; endoplasmic reticulum; inclusion bodies; protein quality control; proteostasis; senescence.