Ripin Lab - The role of Stress Granules and G3BP1 in coupling cytosolic and nuclear stress responses

Stress gran­ules are cyto­solic mem­brane-less orga­nelles com­prised of RNA and RNA bind­ing pro­teins. They form upon a va­riety of dif­ferent stress-ors through the bio­physi­cal prin­ciple of bio­mo­lecu­lar con­den­sa­tion. De­spite the large amount of re­search, the func­tion of stress gran­ules re­mains large­ly un­known. We sug­gest that stress gran­ules act as sig­naling as­sem­blies and will inves­tigate the role of stress gran­ules and its scaf­fold pro­tein G3BP1 in cou­pling cyto­solic and nu-cle­ar stress re­sponses. 

Stress leads to a global trans­lation inhibi­tion, caus­ing ribo­some free RNAs to con­dense into stress gran­ules. G3BP1 and its pa­ralog G3BP2 are the main stress gran­ule as­sem­bly fac­tors and G3BP1/2 knockout abol­ishes stress gran­ules under a va­riety of dif­ferent stresses.

Mul­tiple ob­serva­tions sug­gest that pro­mis­cuous in-ter­mo­lecu­lar RNA-RNA inter­ac­tions con­trib­ute to stress gran­ule as­sem­bly. First, RNAs are large and upon loss of ribo­somes, pro­vide an in­creased num­ber of bind­ing sites. Sec­ond, RNA fold­ing cre­ates sever­al fea­tures that con­trib­ute to in-ter­ac­tions with other RNAs. Fi­nally, all RNA ho­mo­poly­mers can con­dense into drop­lets, tan­gles, or ag­gre­gates in vitro. Simi­larly, total RNA from yeast or mammali­an cells forms RNA con­den­sates under phys­iolog­ical condi­tions with­out any pro­teins. Therefore, pro­mis­cuous RNA-RNA inter­ac­tions or RNA ag­grega­tion con­trib­utes to stress gran­ule for­mation.