Actin filaments—A target for redox regulation

Abstract

Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through non-covalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates – the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL – and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease.

Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons

“…We find here that PlexA3 GAP activity is also essential for cell surface AMPAR downscaling. Plexin signaling can also involve the action of RhoGTPases, several cytosolic kinases, and redox modification of the actin cytoskeleton (Wilson et al, 2016), and future work will address whether any of these signaling components impact postsynaptic homeostatic scaling mechanisms. Our findings here contrast with previous work showing that PlexA4 directly interacts with GluA2 in axons of cultured hippocampal neurons, serving to facilitate GluA2 transport into dendrites and to regulate dendritic branching (Yamashita et al, 2014), and it remains to be determined if this PlexA4 function impacts excitatory synaptic transmission or plasticity.…”

Redox regulation of the actin cytoskeleton and its role in the vascular system

“…Actin itself is susceptible to oxidation and the effects of ROS/RNS on actin function have been extensively studied for almost 70 years [67–70]. As recently reviewed [67], the six cysteines in β/γ-actin and five cysteines in α-actin can all be oxidized, with Cys374 being the most redox-sensitive.…”

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

“…Knowing the precise mechanism of how MICAL proteins act on the actin cytoskeleton and how their activities are fine-tuned in space and time are essential for understanding the physiological functions of MICALs in normal cells, as well as in the context of disease (Wilson et al, 2016).…”

“…We will also review the physiological roles of this emerging class of enzymes on actin-dependent functions, with a special emphasis on their recently demonstrated involvement in cytokinesis (Frémont et al, 2017;Liu et al, 2016;Reinecke et al, 2015). Other biological aspects of the MICAL family are also mentioned briefly and are covered in detail in excellent recent reviews (Giridharan and Caplan, 2014;Wilson et al, 2016).…”

“…1). Members of the MICAL family are multidomain proteins that contain an N-terminal flavoprotein monooxygenase (MO) domain that is essential for its actin-depolymerizing activity (Alqassim et al, 2016;Nadella et al, 2005;Siebold et al, 2005) (see below), a calponin homology (CH) domain typical of actin-binding proteins, a LIM domain (for 'Lin-11, Isl-1 and Mec-3'); and a Rab-binding domain (RBD) with motifs initially proposed to form a coiled-coil domain (Giridharan and Caplan, 2014;Wilson et al, 2016) (Fig. 1).…”