GLA-3 Mediates Stress Response in Caenorhabditis elegans Germ Cells: A key role of the Tristetraprolin (TTP) Family

Tristetraprolin or TTP is an RNA-binding protein that possesses two CCCH-like zinc-finger domains that bind AU-rich elements to promote their degradation. One of its targets is the mRNA of tumor necrosis factor alpha (TNF-). When TTP is absence, the TNF- factor accumulates causing severe, generalized inflammation in knockout mice. TTP is also considered a tumor suppressor protein because regulates the expression of several mRNAs that encode for proteins involve in cell cycle regulation and it is downregulated in various types of human cancers. Under stress, TTP associates with stress granules (SGs), dynamic cytoplasmic condensates formed by liquid-liquid phase separation (LLPS) that protect mRNAs from harmful conditions. Despite TTPs important role in mRNA turnover, much remains to explore about its participation in stress resistance in life animals that is why, we explored the role of GLA-3, one of the TTPs homolog, in the nematode Caenorhabditis elegans. Nematodes lacking gla-3/TTP exhibit phenotypes such as progressive loss of motility, reduced brood size, and increased embryonic lethality. As well as defects in meiotic progression, and increased germ-cell apoptosis. Here we showed that the GFP::GLA-3 reporter is expressed mainly in the C. elegans germline, where associates with different condensates like germ granules, processing bodies, and stress granules suggesting that, like TTP, GLA-3 plays an important role in mRNA regulation in the C. elegans germline. Furthermore we demonstrated that GLA-3 is important for stress granules and processing bodies formation. We also show that oogenic germ cells of GLA-3 mutant animals that were exposed to heat shock resulted embryos that did not survive showing that GLA-3 plays an important role protecting germ cells from this condition. Our results demonstrate that the role of GLA-3 is conserved in C. elegans, and this model can be very useful for further investigating the role of this protein on the future.