Schizosaccharomyces pombe Grx4 is subject to autophagic degradation under nitrogen- and iron- starvation and ER-stress

• Published in: Archives of biochemistry and biophysics Vol. 764; p. 110227
• Main Authors: Li, Rong, Huang, Ying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2025
• Subjects: Autophagy; biophysics; dithiothreitol; domain; endoplasmic reticulum; Endoplasmic Reticulum Stress; ER stress; Glutaredoxins; Glutaredoxins - chemistry; Glutaredoxins - genetics; Glutaredoxins - metabolism; glutathione; heat stability; homeostasis; iron; Iron - metabolism; Iron homeostasis; Nitrogen - metabolism; S. pombe; Schizosaccharomyces - cytology; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; starvation; thiols; transferases; vacuoles; Iron homeostasis; GSSH; Atgs; Grxs; AIM; Glutaredoxins; ER stress; GRX; Autophagy; ER; ER-phagy; S. pombe; CMA; ROS; TRX; GSH; Trxs
• ISSN: 0003-9861; 1096-0384; 1096-0384
• DOI: 10.1016/j.abb.2024.110227

Glutaredoxins (Grxs) are small, heat-stable proteins that serve as multi-functional glutathione （GSH）-dependent thiol transferases. Recent studies have elucidated their role in regulating cellular iron and copper homeostases. In Schizosaccharomyces pombe, five Grxs (Grx1-5) have been identified. Among them， Grx4 and its homologs possess a C-terminal glutaredoxin domain (GRX) and an N-terminal thioredoxin-like domain (TRX). The functional roles of the GRX and TRX domains in Grx4 were investigated by constructing strains that express a truncated Grx4 under the regulation of either a constitutive cam1 promoter or its native promoter. Our findings indicated that two autophagy-related (Atg) protein 8 (Atg8)-interacting motifs (AIM), FLKI and FQEI, in the TRX domain of Grx4 are sufficient to induce autophagic degradation under nitrogen- and iron-starvation, respectively. Moreover, the expression level of a vacuolar ferrous iron transporter Pcl1 was altered in Δatg5 or Δatg8 strains under iron starvation,suggesting that autophagy is required for maintaining iron homeostasis in S. pombe. Further investigations revealed that Grx4 is required for cellular survival and endoplasmic reticulum (ER) autophagy (ER-phagy) during dithiothreitol (DTT) treatment, implying a potential correlation between Grxs and ER-stress. Additionally, loss of Grx4 disrupts nuclear integrity during ER stress, highlighting the versatility and importance of further investigations into the functions of Grx4. [Display omitted] •Grx4 is degraded via autophagy under nitrogen or iron starvation.•The AIM motifs FLKI and FQEI are responsible for the recognition and binding of Atg8 for autophagy.•Autophagic degradation of Grx4 is essential for maintaining iron homeostasis.•Grx4 is required for cellular survival and ER-phagy during DTT treatment.