Gle1 mediates stress granule-dependent survival during chemotoxic stress

Stress granules (SGs) are non-membrane bound organelles that form in response to multiple different stress stimuli, including exposure to sodium arsenite. SGs are postulated to support cells during periods of stress and provide a protective effect, allowing survival. Gle1 is a highly conserved, essential modulator of RNA-dependent DEAD-box proteins that exists as at least two distinct isoforms in human cells. Gle1A is required for proper SG formation, whereas Gle1B functions in mRNA export at the nuclear pore complex. Since Gle1A is required for SG function, we hypothesized that SG-dependent survival responses would also be Gle1-dependent. We describe here an experimental system for quantifying and testing the SG-associated survival response to sodium arsenite stress in HeLa cells. Gle1A was required for the sodium arsenite survival response, and overexpression of Gle1A supported the survival response. Overexpression of the SG-component G3BP also enabled the response. Next, we analyzed whether cells undergoing multiple rounds of stress yield a subpopulation with a higher propensity for SG formation and an increased resistance to undergoing apoptosis. After ten doses of sodium arsenite treatment, cells became resistant to sodium arsenite and to diclofenac sodium (another SG-inducing drug). The sodium arsenite-resistant cells exhibited changes in SG biology and had an increased survival response that was conferred in a paracrine manner. Changes in secreted factors occurred including a significantly lower level of MCP-1, a known regulator of stress granules and stress-induced apoptosis. This study supports models wherein SGs play a role in cell evasion of apoptosis and further reveal Gle1A and SG functions as targets for clinical approaches directed at chemoresistant/refractory cells.