SelR reverses Mical-mediated oxidation of actin to regulate F-actin dynamics

Abstract

Actin's polymerization properties are dramatically altered by oxidation of its conserved methionine (Met)-44 residue. Mediating this effect is a specific oxidation-reduction (Redox) enzyme, Mical, that works with Semaphorin repulsive guidance cues and selectively oxidizes Met-44. We now find that this actin regulatory process is reversible. Employing a genetic approach, we identified a specific methionine sulfoxide reductase enzyme SelR that opposes Mical Redox activity and Semaphorin/Plexin repulsion to direct multiple actin-dependent cellular behaviors in vivo. SelR specifically catalyzes the reduction of the R-isomer of methionine sulfoxide (methionine-R-sulfoxide) to methionine, and we found that SelR directly reduced Mical-oxidized actin, restoring its normal polymerization properties. These results indicate that Mical oxidizes actin stereo-specifically to generate actin Met-44-R-sulfoxide (actinMet(R)O-44) – and they also implicate the interconversion of specific Met/Met(R)O residues as a precise means to modulate protein function. Our results therefore uncover a specific reversible Redox actin regulatory system that controls cell and developmental biology.

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

“…They are widely expressed in nervous system and other tissues, including endothelial cells and cancer cells such as melanoma and HeLa cells 4, 5, 6, 7. Although MICAL family is identified as MICAL (1‐3) and MICAL‐like (‐L1, ‐L2) forms in mammals, its main functions were studied mostly in Drosophila 1, 3, 8. Normally, MICAL family members have four conserved domains: N‐terminal flavin adenine dinucleotide (FAD) binding domain, Lin11, Isl‐1 and Mec‐3 (LIM) domain, calponin homology (CH) domain and C‐terminal coiled‐coil (CC) domain.…”

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis

“…Interestingly, MICAL-mediated actin oxidation is selectively reversed by methionine sulfoxide reductases (SelR in Drosophila, MsrB proteins in mammals), which prevent F-actin disassembly induced by MICALs in vitro (Hung et al, 2013;Lee et al, 2013). Consistent with this, SelR counteracts Mical in multiple actin-dependent cellular processes in Drosophila, including axon guidance, synaptogenesis, muscle organization and mechanosensory development (Hung et al, 2013). In mammals, MsrB1 has a regulatory role as a MICAL1 antagonist in orchestrating actin dynamics and macrophage function (Lee et al, 2013).…”

“…In addition, a direct contact between MICALs and F-actin appears to be compulsory for depolymerization, whereas incubation with high concentrations of H 2 O 2 (40 mM) alone are insufficient to depolymerize actin filaments (Frémont et al, 2017;Hung et al, 2011). Interestingly, MICAL-mediated actin oxidation is selectively reversed by methionine sulfoxide reductases (SelR in Drosophila, MsrB proteins in mammals), which prevent F-actin disassembly induced by MICALs in vitro (Hung et al, 2013;Lee et al, 2013). Consistent with this, SelR counteracts Mical in multiple actin-dependent cellular processes in Drosophila, including axon guidance, synaptogenesis, muscle organization and mechanosensory development (Hung et al, 2013).…”

“…2). For example, MICAL proteins are required for several aspects of neuronal biology (Beuchle et al, 2007;Bron et al, 2007;Hung et al, 2013Hung et al, , 2010Kirilly et al, 2009;Lundquist et al, 2014;Luo et al, 2011;Morinaka et al, 2011;Pasterkamp et al, 2006;Schmidt et al, 2008;Terman et al, 2002;Van Battum et al, 2014), cell viability (Ashida et al, 2006;Loria et al, 2015;Zhou et al, 2011), cancer (Deng et al, 2016;Loria et al, 2015;Mariotti et al, 2016), immunity (Lee et al, 2013), skeletal muscle morphology and function (Beuchle et al, 2007;Hung et al, 2013), cardiovascular integrity , bristle development (Hung et al, 2011(Hung et al, , 2013, cell shape (Aggarwal et al, 2015;Giridharan et al, 2012b), membrane trafficking (Bachmann-Gagescu et al, 2015;Grigoriev et al, 2011) and regulation of nuclear actin (Lundquist et al, 2014). The newly described roles of MICAL family members in cytokinesis will be discussed in detail below.…”

Semaphorin signalling during development

“…Studies have shown that members of the MICAL family of redox enzymes (Zhou et al, 2011) can bind to the cytosolic part of plexins and induce F-actin disassembly by mediating the post-translational oxidation of actin filament subunits (Hung et al, 2010. Intriguingly, this process is antagonised by the methionine sulfoxide reductase SelR, which reduces oxidised actin and thereby promotes F-actin assembly (Hung et al, 2013). MICALs and SelR thus provide plexin receptors with the ability to directly redox modify F-actin upon semaphorin binding.…”