Projekt

Role of the WAVE complex in the immune system

Actin branching at the cell periphery depends on WAVE- and Arp2/3-complexes. Our group has a long history in WAVE-complex research and contributed significantly to the elucidation of its function. Over the years, we analyzed tissue-cultured cells suppressed in the expression of its subunits by RNA-interference or genetic deletion. To unambiguously clarify the role of WAVE-complex and thus lamellipodia in vivo, we decided to target WAVE-complex in the immune system, where motile cells fulfil defined functions while showing different types of motile behavior. Deletion of Hem1 results in the loss of WAVE-complex and consequently lamellipodium formation in all immune cells. Strikingly, Hem1 deletion eliminates chemotaxis. In complex 3D-environments, lamellipodia mediate exploration of the environment. Consequently, Hem1-null cells can no longer make directional decisions, persistently crawl in one direction and thus likely become trapped in narrow pores. These trapped yet activated innate immune cells then cause local sterile inflammation. Dendritic cells derived from these mice show abberant migratory behavior and fail to perform interstitial migration and chemotaxis (Leithner et al., 2016, Thiam et al., 2016).

Dendritic cells that lack Hem1 and consequently WAVE-complex do not form lamellipodial protrusions. Although motile, they fail to explore their environment and thus to effectively reach their destination (image adapted from Leithner et al., 2016).Relevant publications concerning this project:

I. Leithner A, Eichner A, Müller J, Reversat A, Brown M, Schwarz J, Merrin J, de Gorter DJ, Schur F, Bayerl J, de Vries I, Wieser S, Hauschild R, Lai FP, Moser M, Kerjaschki D, Rottner K, Small JV, Stradal TE, Sixt M (2017) Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. Nat Cell Biol 18(11): 1253-59.

II. Thiam HR, Vargas P, Carpi N, Crespo CL, Raab M, Terriac E, King MC, Jacobelli J, Alberts AS, Stradal T, Lennon-Dumenil AM, Piel M (2016) Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. Nat Commun 7: 10997.

III. Kage F, Winterhoff M, Dimchev V, Mueller J, Thalheim T, Freise A, Brühmann S, Kollasser J, Block J, Dimchev G, Geyer M, Schnittler HJ, Brakebusch C, Stradal TE, Carlier MF, Sixt M, Käs J, Faix J, Rottner K (2017) FMNL formins boost lamellipodial force generation. Nat Commun 8:14832.

IV. Rottner K, Stradal TE (2016) How distinct Arp2/3 complex variants regulate actin filament assembly. Nat Cell Biol 18(1): 1-3.

V. Litschko C, Linkner J, Brühmann S, Stradal TEB, Reinl T, Jänsch L, Rottner K, Faix J (2017) Differential functions of WAVE regulatory complex subunits in the regulation of actin-driven processes. Eur J Cell Biol 96(8): 715-27.

VI. Steffen A, Ladwein M, Dimchev GA, Hein A, Schwenkmezger L, Arens S, Ladwein KI, Margit Holleboom J, Schur F, Victor Small J, Schwarz J, Gerhard R, Faix J, Stradal TE, Brakebusch C, Rottner K (2013) Rac function is crucial for cell migration but is not required for spreading and focal adhesion formation. J Cell Sci 126(Pt 20): 4572-88.

VII. Tahirovic S, Hellal F, Neukirchen D, Hindges R, Garvalov BK, Flynn KC, Stradal TE, Chrostek-Grashoff A, Brakebusch C, Bradke F (2010) Rac1 regulates neuronal polarization through the WAVE complex. J Neurosci 30(20): 6930-43.

VIII. Derivery E, Fink J, Martin D, Houdusse A, Piel M, Stradal TE, Louvard D, Gautreau A (2008) Free Brick1 is a trimeric precursor in the assembly of a functional wave complex. PLoS ONE 3(6): e2462.

IX. Steffen A, Faix J, Resch GP, Linkner J, Wehland J, Small JV, Rottner K, Stradal TE (2006) Filopodia formation in the absence of functional WAVE- and Arp2/3-complexes. Mol Biol Cell 17(6): 2581-91.

X. Stradal TE, Scita G (2006) Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol 18(1): 4-10.

XI. Innocenti M, Gerboth S, Rottner K, Lai FP, Hertzog M, Stradal TE, Frittoli E, Didry D, Polo S, Disanza A, Benesch S, Di Fiore PP, Carlier MF, Scita G (2005) Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nat Cell Biol 7(10): 969-76.

XII. Innocenti M, Zucconi A, Disanza A, Frittoli E, Areces LB, Steffen A, Stradal TE, Di Fiore PP, Carlier MF, Scita G (2004) Abi1 is essential for the formation and activation of a WAVE2 signalling complex.  Nat Cell Biol 6(4): 319-27.

XIII. Steffen A, Rottner K, Ehinger J, Innocenti M, Scita G, Wehland J, Stradal TE (2004) Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation. EMBO J 23(4): 749-59.

XIV. Kaverina I, Stradal TE, Gimona M (2003) Podosome formation in cultured A7r5 vascular smooth muscle cells requires Arp2/3-dependent de-novo actin polymerization at discrete microdomains. J Cell Sci 116(Pt 24): 4915-24.

XV. Small JV, Stradal T, Vignal E, Rottner K (2002) The lamellipodium: where motility begins. Trends Cell Biol 12(3): 112-20.

XVI. Stradal T, Courtney KD, Rottner K, Hahne P, Small JV, Pendergast AM (2001) The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia. Curr Biol 11(11): 891-5.