Dynein and kinesin regulate stress-granule and P-body dynamics

Abstract

Stress granules (SGs) and P-bodies (PBs) are related cytoplasmic structures harboring silenced mRNAs. SGs assemble transiently upon cellular stress, whereas PBs are constitutive and are further induced by stress. Both foci are highly dynamic, with messenger ribonucleoproteins (mRNPs) and proteins rapidly shuttling in and out. Here, we show that impairment of retrograde transport by knockdown of mammalian dynein heavy chain 1 (DHC1) or bicaudal D1 (BicD1) inhibits SG formation and PB growth upon stress, without affecting protein-synthesis blockage. Conversely, impairment of anterograde transport by knockdown of kinesin-1 heavy chain (KIF5B) or kinesin light chain 1 (KLC1) delayed SG dissolution. Strikingly, SG dissolution is not required to restore translation. Simultaneous knockdown of dynein and kinesin reverted the effect of single knockdowns on both SGs and PBs, suggesting that a balance between opposing movements driven by these molecular motors governs foci formation and dissolution. Finally, we found that regulation of SG dynamics by dynein and kinesin is conserved in Drosophila.

mRNP granules

“…For instance, microtubule depolymerizing drugs prevent assembly of large stress granules 39,40 and germ granules in early zebrafish embryos, 41 whereas P-bodies become larger, and less mobile. 42,43 Specific dynein and kinesin motor proteins also localize in stress granules, and appear to facilitate assembly and disassembly of stress granules, respectively.…”

“…42,43 Specific dynein and kinesin motor proteins also localize in stress granules, and appear to facilitate assembly and disassembly of stress granules, respectively. 40 Dynein proteins also increase P-body assembly under stress. 40 Contrasting results have been observed upon stress granule assembly following disruption of actin, 40,44 while P-body disassembly in yeast is slowed by mutation of a myosin type V protein, Myo2.…”

“…40 Dynein proteins also increase P-body assembly under stress. 40 Contrasting results have been observed upon stress granule assembly following disruption of actin, 40,44 while P-body disassembly in yeast is slowed by mutation of a myosin type V protein, Myo2. 45 It is additionally very clear that localization of various germ and transport granules makes use of cytoskeletal elements for translocation and anchoring at specific sites; this subject has been well covered elsewhere.…”

Cytoplasmic mRNP granules at a glance

“…Some evidence indicates a role for the cytoskeleton in PB and SG dynamics. For example, microtubule-depolymerizing drugs can lead to impaired SG formation (Fujimura et al, 2009;Ivanov et al, 2003;Kolobova et al, 2009;Kwon et al, 2007;Loschi et al, 2009), impaired SG and PB movement, and enlarged PBs (Aizer et al, 2008;Sweet et al, 2007). By contrast, actin depolymerization does not affect SG assembly (Ivanov et al, 2003;Kwon et al, 2007) and PBs associated with actin in human cells do not appear mobile (Aizer et al, 2008).…”

“…Microtubule motor proteins can also affect SG and PB dynamics. Inhibition of dynein function can lead to impaired SG formation and enlarged PBs in response to stress (Kwon et al, 2007;Loschi et al, 2009;Tsai et al, 2009), whereas depletion of kinesins can delay the disassembly of SGs and rescue the assembly defects caused by dynein depletion (Loschi et al, 2009). Although these observations suggest functional interplay between SGs and PBs and the cytoskeleton, pleiotropic effects arising from cytoskeletal manipulation make it difficult to pinpoint its importance and relevance.…”