Translational Repression of G3BP in Cancer and Germ Cells Suppresses Stress Granules and Enhances Stress Tolerance

• Published in: Molecular cell Vol. 79; no. 4; pp. 645 - 659.e9
• Main Authors: Lee, Anna K., Klein, Jonathon, Fon Tacer, Klementina, Lord, Tessa, Oatley, Melissa J., Oatley, Jon M., Porter, Shaina N., Pruett-Miller, Shondra M., Tikhonova, Elena B., Karamyshev, Andrey L., Wang, Yong-Dong, Yang, Peiguo, Korff, Ane, Kim, Hong Joo, Taylor, J. Paul, Potts, Patrick Ryan
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.08.2020
• Subjects: cancer; cancer-testis antigen; DDX5; G3BP; MAGE-B2; RNA binding protein; spermatogonial stem cells; stress granule; testis; translation; DDX5; spermatogonial stem cells; stress granule; RNA binding protein; MAGE-B2; translation; cancer; G3BP; testis; cancer-testis antigen
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.06.037

Stress granules (SGs) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SGs act as a protective mechanism to cope with acute stress, but persistent SGs have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP1 confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermosensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress and could aid in the development of male fertility therapies. [Display omitted] •Decreased G3BP reduces stress granule formation and increases stress tolerance•MAGE-B2 represses G3BP mRNA translation by displacing DDX5 helicase from the 5′ UTR•The mouse ortholog of MAGE-B2 regulates stemness of testis spermatogonial stem cells•Excess G3BP results in hypersensitivity to heat stress and reduced fertility in vivo Lee et al. demonstrate that the testis-specific protein MAGE-B2 increases stress tolerance by suppressing stress granule formation through translational inhibition of the stress granule nucleator G3BP. Knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP confers hypersensitivity of the male germline to heat stress in vivo.