Stress Granule is a special kind of membrane-free aggregates in eukaryotic cells, mainly composed of mRNA, RNA-binding protein, etc. Itis the main intracellular mRNA ribonucleoprotein (mRNP) granule. When cells are stimulated by adverse conditions (including oxidative stress, changes in osmotic pressure, heat stress, protein stress, etc.), the stress granules assemble in the cytoplasm in an orderly manner and are disassembled in a regulated manner after the stress is removed. It follows that stress granules are a dynamic, reversible and unique cytoprotective and adaptive mechanism. In 2021, Taylor JP's group identified a central role for protein ubiquitination networks in the de-assembly of stress granules and found that ubiquitination of the constitutive protein G3BP1 dominated the de-assembly of stress granules under heat stress conditions. The regulatory network of intracellular ubiquitination is large and complex, and the molecular regulatory mechanisms that regulate stress granule deassembly still need to be investigated in depth.

On 13 April 2023, Professor YUAN Shuiqiao's group at the Institute of Reproductive Health published an article entitled "SERBP1 promotes stress granule clearance by regulating 26S proteasome activity and G3BP1 ubiquitination and protects male germ cells from thermostimuli damage "The research paper. The paper identifies a novel RNA-binding protein, SERBP1, that regulates stress granule dynamics and finds that SERBP1 can be localised to a variety of stimulus-induced stress granules and that knocking down the Serbp1 gene significantly reduces the efficiency of stress granule deassembly during recovery. FAF2 localization on stress granules. More importantly, in mouse spermatogenic cells, SERBP1 also localizes to stress granules and protects germ cell survival after testicular heat stress.

In this study, YUANShuiqiao's group first discovered that the RNA-binding protein Serbp1 co-localized with the multiple stimulus-induced stress granule marker protein G3BP1, and that the RRM structural domain mediated the recruitment process. Knockdown of Serbp1 in HeLa cells did not affect the formation of sodium arsenite or heat stress-induced stress granules in the cytoplasm, but the proportion of knockdown cells containing stress granules increased significantly during the recovery period after removal of stimuli, suggesting that SERBP1 is involved in the de-assembly regulation process.

To investigate the molecular mechanism of impaired stress granule deactivation due to Serbp1 knockdown, the group found that SERBP1 could interact with several subunits of the proteasome through immunoprecipitation assays. Further studies revealed that SERBP1 directly regulates proteasome activity during stress particle deactivation, which is a key link in regulating stress particle deactivation. Furthermore, specifically during heat stress-induced stress particle deactivation, SERBP1 could affect the ubiquitination level of the core protein G3BP1, which in turn mediated its interaction with the downstream proteins VCP and FAF2. More importantly, SERBP1 protected the survival of germ cells to a certain extent after heat stress in mouse testis, suggesting a potential physiological function of SERBP1 in regulating stress granule dynamics in germ cell development.

In summary, this study is the first to propose an important role for the RNA-binding protein SERBP1 in the process of stress granule deassembly and to elucidate the molecular mechanism of its role; and to innovatively investigate its role in the protection of germ cells from heat stress, providing new evidence for the physiological function of stress granule dynamics (Figure 1).

Figure 1. Hypothetical model of SERBP1 regulation of

intracellular stress granule de-assembly

The Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology is the first author of this research paper. Associate Professor WANG Fengli from the Institute of Reproductive Health, PhD student WANG Lingjuan from the class of 2019 (now working in Nanjing Gulou Hospital) and PhD student GAN Shiming from the class of 2021 are the co-first authors of the paper, and Professor YUAN Shuiqiao is the sole corresponding author of the paper. The research was supported by the National Natural Science Foundation of China under the Youth Program and the Surface Program.

Paper link：https://spj.science.org/doi/full/10.34133/research.0091