Regulation of ER-phagy during cellular stresses

The National Institute of General Medical Sciences awarded the University of Texas Health Science Center at Houston $429,000 on March 6, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the regulation of ER-phagy during cellular stresses.

The research comprises two programs. Program 1 examines the ER-phagy receptor TEX264, focusing on its interaction with P62, an autophagy receptor for ubiquitinated cargos, and how this interaction facilitates ER-phagy during starvation to reveal cooperation between autophagy receptors in regulating ER-phagy. Program 2 explores ERLIN-2, a component of the ER membrane-associated ERLIN complex involved in ER-associated degradation, as a potential ER-phagy receptor, determining whether ERLIN-2 recruits autophagy machinery to assist in degradation of ERAD substrates under stress conditions.

Work is performed in Houston, Texas. The period of performance runs from March 6, 2026, through February 28, 2031. The award is classified as a Project Grant.

Abstract

Autophagy is a lysosomal degradation pathway that breaks down and recycles unwanted and dysfunctional cellular components, known as autophagy cargos. Autophagy is essential for maintaining cellular and organismal homeostasis, and its dysregulation has been implicated in various pathological conditions, including neurodegeneration, infectious diseases, metabolic disorders and cancer. Autophagy can selectively degrade specific cytoplasmic cargos, and this cargo selection process is mediated by cargo receptors. Like other organelles, the endoplasmic reticulum (ER) undergoes selective autophagic degradation, a process known as ER-phagy, which is crucial for ER quality control and remodeling. Several ER-phagy receptors have been identified, which are localized to distinct ER subdomains, thereby targeting specific ER regions for degradation under different conditions. Given the fundamental roles of ER in protein and lipid synthesis, ION homeostasis, and inter-organelle communication, ER-phagy must be tightly regulated to maintain ER function. However, the mechanisms by which ER-phagy receptors orchestrate and fine-tune this process in response to cellular stress remain incompletely understood. This proposal aims to address these gaps through two research programs. In program 1, i will investigate the well-characterized ER-phagy receptor TEX264, focusing on its interaction with P62, an autophagy receptor for ubiquitinated cargos, and how this interaction facilitates ER-phagy during starvation. This study will provide new insights into the cooperation between autophagy receptors in regulating ER-phagy. In program 2, i will explore erlin-2, a component of the ER membrane-associated erlin complex involved in ER-associated degradation (erad), as a potential ER-phagy receptor. Specifically, i aim to determine whether erlin-2 recruits autophagy machinery to assist in the degradation of erad substrates under stress conditions such as starvation and ER stress. This study will establish a direct mechanistic link between erad and ER-phagy pathways. The flexibility of the mira grant will enable the simultaneous pursuit of both programs. Collectively, these studies will provide a deeper understanding of ER-phagy regulation and its role in cellular stress responses.