Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation

Proteotoxicity induced by misfolded or aggregated proteins causes progressive neuronal damage. The endoplasmic reticulum (ER) protein quality control (ERQC) pathways are responsible for mitigating the accumulation of these misfolded or aggregated proteins, thus reducing proteotoxicity. Enhancing ERQC pathways is a promising strategy for treating neurodegenerative diseases. However, the mechanisms governing the initiation and degradation of misfolded or aggregated proteins in neurons remain largely unknown in vivo. In studying the maturation of proAVP in mouse AVP neurons, this study discovers that autophagy and ER-associated degradation (ERAD) ERQC pathways collaborate to maintain proAVP maturation and protect AVP neuron survival against proteotoxicity. Autophagy deficiency in mouse AVP neurons leads to the late-onset of diabetes insipidus. Mechanistically, autophagy selectively degrades mutant proAVP aggregates and endogenous HRD1 of the SEL1L-HRD1 ERAD complex through FAM134B mediated ER-phagy. HRD1 induction is responsible for reducing proAVP aggregation and maintaining AVP neuron function and survival under autophagy deficiency. Thus, autophagy and ERAD form a dual-protection system that orchestrates prohormone maturation and endocrine neuron survival, providing new insights in the complexity of neuroendocrinology and the intrinsic mechanism of neurodegenerative diseases, with therapeutic potential in protein folding diseases.

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Publication Details

Journal
Advanced Science
Published
2025-03-07
DOI
https://doi.org/10.1002/advs.202411662
Citations
2
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
2.30

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article

Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation

Jifeng Yang, Guojun Shi, Jun Cui, Na Xiong et al.
2 citations
Advanced Science
Endoplasmic Reticulum Stress and Disease
2.30
article

Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation

Jifeng Yang, Guojun Shi, Jun Cui, Na Xiong, Martin Spiess, Heting Wang, Diane Somlo, Xuya Pan, Shasha Li, Haiyang Wang, Ling Qi, Yanming Chen, Su Wu, Wenbin Ma, Chunliang Li, Xinyu Hou, Xing He
article en
2 citations

Abstract

Proteotoxicity induced by misfolded or aggregated proteins causes progressive neuronal damage. The endoplasmic reticulum (ER) protein quality control (ERQC) pathways are responsible for mitigating the accumulation of these misfolded or aggregated proteins, thus reducing proteotoxicity. Enhancing ERQC pathways is a promising strategy for treating neurodegenerative diseases. However, the mechanisms governing the initiation and degradation of misfolded or aggregated proteins in neurons remain largely unknown in vivo. In studying the maturation of proAVP in mouse AVP neurons, this study discovers that autophagy and ER-associated degradation (ERAD) ERQC pathways collaborate to maintain proAVP maturation and protect AVP neuron survival against proteotoxicity. Autophagy deficiency in mouse AVP neurons leads to the late-onset of diabetes insipidus. Mechanistically, autophagy selectively degrades mutant proAVP aggregates and endogenous HRD1 of the SEL1L-HRD1 ERAD complex through FAM134B mediated ER-phagy. HRD1 induction is responsible for reducing proAVP aggregation and maintaining AVP neuron function and survival under autophagy deficiency. Thus, autophagy and ERAD form a dual-protection system that orchestrates prohormone maturation and endocrine neuron survival, providing new insights in the complexity of neuroendocrinology and the intrinsic mechanism of neurodegenerative diseases, with therapeutic potential in protein folding diseases.

Advanced ScienceVol. 12(23)
South China Agricultural University (CN), St. Jude Children's Research Hospital (US), Sun Yat-sen University (CN), University of Basel (CH), Massachusetts General Hospital (US), Sun Yat-sen Memorial Hospital (CN), Sun Yat-sen University Cancer Center (CN), Third Affiliated Hospital of Sun Yat-sen University (CN), University of Virginia (US)
Foundation for the National Institutes of Health, National Natural Science Foundation of China, Guangzhou Municipal Science and Technology Project, Key Technologies Research and Development Program, Fundamental Research Funds for the Central Universities, Basic and Applied Basic Research Foundation of Guangdong Province
Good health and well-being
Openalex Percentile: Top 15%
Endoplasmic Reticulum Stress and Disease
2.30
DOIOpen Access PDFOpenAlex
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