Stress granules are membraneless condensates of RNA and RNA-binding proteins formed in response to cell stress. New evidence of the relationship between stress granules and neurodegenerative diseases highlights their physiological importance. Therefore, understanding the mechanism of this association and determining the key players that control stress granule homeostasis are crucial to the development of treatment methods for these diseases.
On January 24th, a research article entitled “Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules” was published online in the journal Autophagy. This work was led by professors Liu Yanfen and Bai Yun from the School of Life Science and Technology (SLST) at ShanghaiTech University. In this study, the intrinsic mechanism of physiological and pathological stress granule homeostasis regulation was discovered, suggesting a new potential target for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
The prevalence of several quality control proteins in stress granules indicates that the compartment is strictly monitored. Liu’s group screened six E3 ligases that exist in stress granules, and identified TRIM21 (tripartite motif containing 21) as the central regulator of stress granule homeostasis, and it is highly enriched in stress granules under oxidative stress.
TRIM21 has previously been reported to participate in the ubiquitin-mediated autophagic degradation of a couple of innate immune responsive effectors. Liu’s group found that TRIM21 mediates lysine 63-linked ubiquitination of the stress granule core protein G3BP1, which subsequently inhibits stress granule formation. In contrast, TRIM21 knockdown leads to a decrease in the level of ubiquitin binding to G3BP1 and promotes the formation of stress granules.
Furthermore, the researchers found that stress granule homeostasis is also regulated by autophagy. Autophagy is a highly conserved intracellular pathway involved in the disposal of protein aggregates, damaged organelles and invasive pathogens through lysosomal degradation. This study provides evidence for SQSTM1 and CALCOCO2 being the primary autophagy receptors in autophagic clearance of physiological and pathological stress granules.
Fifth year Ph.D. candidate Yang Cuiwei, third year Ph.D. candidate Wang Zhangshun and Research Assistant Kang Yingjin of Liu’s group are the co-first authors of the paper. Assistant Professor Liu Yanfen and Assistant Professor Bai Yun are the corresponding authors. ShanghaiTech is the first affiliation.
Model of TRIM21 and autophagy machinery in regulating the homeostasis of stress granules.
**This news article is provided by Liu Yanfen