Response to stress in biological disorders: Implications of stress granule assembly and function

Abstract

It is indispensable for cells to adapt and respond to environmental stresses, in order for organisms to survive. Stress granules (SGs) are condensed membrane-less organelles dynamically formed in the cytoplasm of eukaryotes cells to cope with diverse intracellular or extracellular stress factors, with features of liquid-liquid phase separation. They are composed of multiple constituents, including translationally stalled mRNAs, translation initiation factors, RNA-binding proteins and also non-RNA-binding proteins. SG formation is triggered by stress stimuli, viral infection and signal transduction, while aberrant assembly of SGs may contribute to tissue degenerative diseases. Recently, a growing body of evidence has emerged on SG response mechanisms for cells facing high temperatures, oxidative stress and osmotic stress. In this review, we aim to summarize factors affecting SGs assembly, present the impact of SGs on germ cell development and other biological processes. We particularly emphasize the significance of recently reported RNA modifications in SG stress responses. In parallel, we also review all current perspectives on the roles of SGs in male germ cells, with a particular focus on the dynamics of SG assembly.

Keywords: assembly; biological disorders; germ cells; heat stress; stress granules.

FIGURE 1

Factors affecting stress granule (SG) assembly and the function of SG. Post‐transcriptional modifications (m⁶A and m¹A), RNA interaction, the network of microtubules, protein interactions, protein modifications and liquid‐liquid phase separation all impact SG assembly are shown. SGs function as cellular protection, prevent cell apoptosis and sequestrate components. m⁶A, N⁶‐methyladenosine; m¹A, N¹‐methyladenosine

FIGURE 2

Schematic illustration for heat stress in male germ cells. Heat stress induces stress granule (SG) formation by phosphorylating eIF2α, recruiting RNA binding protein (DAZL, BOULE, RACK) and ultimately protecting normal spermatogenesis from germ cell apoptosis. In addition, MAGE‐B2, a testis‐specific protein, can enhance stress tolerance by modulating SG formation. BOULE, a founding member of the DAZ gene family; DAZL, deleted in azoospermia‐like; eIF2α, eukaryotic initiation factor‐2alpha; MAGE‐B2, testis‐specific protein; MAPK, mitogen‐activated protein kinases; RACK, receptor for activated protein kinase C

FIGURE 3

Areas in which stress granules (SGs) are involved. SGs function in male fertility and play roles in other biological and pathological processes, such as inflammatory response, Alzheimer's disease, viral infection, cancer and atrial fibrillation. Spermatogenesis is affected by heat stress in the testicles outside the body cavity. RNA‐binding proteins (DAZL) can be recruit to SGs, which protect male fertility. Pro‐inflammatory cytokines (IFN‐γ and TNF‐α) induce eIF2α phosphorylation and SGs formation, while anti‐inflammatory cytokine (il‐19) inhibit the formation of SG. Misfolded RNA binding proteins (such as TDP43) aggregate abnormally and further induce aberrant SG formation, which results in Alzheimer's disease. SGs can inhibit viral replication by isolating relevant components (eIF4E, eIF4G and 40S ribosome subunit). HuR and TTP are important components of SGs. Overexpression of HuR in cancer cells leads to tumour enlargement, while TTP plays an anti‐tumour role. SGs exist in atrial myocytes of AF, which can reduce ROS and calcium overload levels. AF, Atrial fibrillation; eIF4E, eIF4G, eukaryotic translation initiation factor 4E/G; HuR, Hu antigen R; IFN‐γ, interferon; il‐19, interleukin‐19; ROS, reactive oxygen species; TDP43,TAR DNA‐binding protein 43; TNF‐α, tumour necrosis factor alpha; TTP, tristetraprolin