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

2020; Elsevier BV; Volume: 79; Issue: 4 Linguagem: Inglês

10.1016/j.molcel.2020.06.037

1097-4164

Anna K. Lee, Jonathon Klein, Klementina Fon Tacer, Tessa Lord, Melissa J. Oatley, Jon M. Oatley, Shaina N. Porter, Shondra M. Pruett‐Miller, Elena B. Tikhonova, Andrey L. Karamyshev, Yong‐Dong Wang, Peiguo Yang, Ané Korff, Hong Joo Kim, J. Paul Taylor, Patrick Ryan Potts,

RNA modifications and cancer

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.