Dictyostelium huntingtin controls chemotaxis and cytokinesis through the regulation of myosin II phosphorylation

Abstract

This work shows that huntingtin protein (Htt) regulates the phosphorylation status of myosin II during chemotaxis and cytokinesis through protein phosphatase 2A (PP2A). Our findings provide novel insights into the physiological function of Htt and the pathogenesis of Huntington's disease.

Huntingtin regulates Ca2+ chemotaxis and K+-facilitated cAMP chemotaxis, in conjunction with the monovalent cation/H+ exchanger Nhe1, in a model developmental system: Insights into its possible role in Huntington׳s disease

“…These results suggest that they both play a role in a process common to the two behaviors. The observation that both htt À (Myre et al, 2011;Wang et al, 2011b; data presented here) and nhe1 À cells (Patel and Barber, 2005;Lusche et al, 2012; data presented here) exhibit abnormalities in cell polarization, actin localization as well as cAMP induced actinpolymerization, and that Nhe1 is delocalized in the htt À mutant, suggest that both are necessary for normal actin-myosin localization in these two common behaviors, and that Nhe1 depends directly or indirectly on Htt for localization in an anterior pseudopod. We did not expect to find that Htt was essential for K þ -facilitated cAMP chemotaxis, but not Ca 2 þ -facilitated cAMP chemotaxis, given the association of huntingtin with Ca 2 þ homeostasis in human cells (Cattaneo et al, 2005).…”

“…Consequently, the model developmental organism D. discoideum (Williams et al, 2006; Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/developmentalbiology Myre, 2012;Müller-Taubenberger et al, 2013;Muñoz-Braceras et al, 2013;Annesley et al, 2014), which undergoes cellular locomotion and chemotaxis in a manner similar to human cells (Cai and Devreotes, 2011;Wang et al, 2011a;Jin, 2013), has been used to explore the role of huntingtin at the cellular level. Wang et al (2011b) and Myre et al (2011) independently disrupted htt, the ortholog of human HTT, in D. discoideum. Normally, populations of D. discoideum amoebae, when starved for nutrients on a substrate, aggregate by undergoing chemotaxis in response to relayed outwardly moving, nondissipating waves of the chemoattractant cAMP, released in a pulsatile fashion from aggregation centers (Konijin et al, 1967;Gerisch et al, 1975;Tomchik and Devreotes, 1981).…”

“…Chemotactic orientation in the increasing spatial gradient of cAMP in the front of each relayed wave in a natural aggregation territory is facilitated by chemotaxis up steep transient Ca 2 þ gradients generated between cells in response to the onset of the front of each cAMP wave (Scherer et al, 2010). Both Wang et al (2011b) and Myre et al (2011) showed that htt À cells were defective in chemotaxis in a spatial gradient of cAMP generated in vitro.…”

Rho GTPases orient directional sensing in chemotaxis

“…A chemotaxis assay was performed as described (17,38,39,57). Cells were cultured in HL5 medium on Petri dishes, washed twice with DB, resuspended to 2 × 10 7 cells/mL, and shaken for 1 h before being induced to differentiate with 100 nM cAMP pulses at 6-min intervals for 4 h. Differentiated cells were plated on a chambered coverslip (Lab-Tek; Nalgen Nunc).…”

Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes

“…MHC phosphorylation is reversible, and dephosphorylation is mediated by the phosphatase PP2A [259]. The importance of this regulation is highlighted in cells that lack the huntingtin protein [260]. These cells have reduced PP2A activity, reduced myosin II disassembly, and aberrant chemotaxis.…”