Signaling Components of Redox Active Endosomes: The Redoxosomes

Abstract

Subcellular compartmentalization of reactive oxygen species (ROS) plays a critical role in transmitting cell signals in response to environmental stimuli. In this regard, signals at the plasma membrane have been shown to trigger NADPH oxidase-dependent ROS production within the endosomal compartment and this step can be required for redox-dependent signal transduction. Unique features of redox-active signaling endosomes can include NADPH oxidase complex components (Nox1, Noxo1, Noxa1, Nox2, p47phox, p67phox, and=or Rac1), ROS processing enzymes (SOD1 and=or peroxiredoxins), chloride channels capable of mediating superoxide transport and=or membrane gradients required for Nox activity, and novel redox-dependent sensors that control Nox activity. This review will discuss the cytokine and growth factor receptors that likely mediate signaling through redox-active endosomes, and the common mechanisms whereby they act. Additionally, the review will cover ligand-independent environmental injuries, such as hypoxia=reoxygenation injury, that also appear to facilitate cell signaling through NADPH oxidase at the level of the endosome. We suggest that redox-active endosomes encompass a subset of signaling endosomes that we have termed redoxosomes. Redoxosomes are uniquely equipped with redox-processing proteins capable of transmitting ROS signals from the endosome interior to redox-sensitive effectors on the endosomal surface. In this manner, redoxosomes can control redoxdependent effector functions through the spatial and temporal regulation of ROS as second messengers. Antioxid. Redox Signal. 11, 1313-1333

Peroxiredoxin Functions as a Peroxidase and a Regulator and Sensor of Local Peroxides

“…One possible explanation was localized production of H 2 O 2 . Evidence indicates that NADPH oxidase (Nox) is largely responsible for receptor-dependent H 2 O 2 production (55,56) and that Nox1 and Nox2 are activated within lipid rafts, which serve as a platform for the assembly of various signaling proteins, including receptor PTKs and Src family kinases (57). EtOH feeding increases the abundance of CYP2E1 in the ER.…”

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

“…Although these receptors have unique effector pathways responsible for activating NFkB, they share a similar dependence on redox-active signaling endosomes for their activation cascades. For these reasons, redox-active signaling endosomes have been recently named redoxosomes (103). The mechanisms of redoxosome activation may be particular relevant to redox-signaling in ALS.…”

“…Activation of the IKK complex then leads to phosphorylation of IkB (inhibitor of NFkB) and subsequent mobilization of NFkB to the nucleus, where it can transcriptionally activate pro-inflammatory pathways. For a more comprehensive review on the effectors of both the IL-1R and TNFR1 pathways that lead to redoxosomal activation of NFkB, see the review by Oakley (103).…”

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

“…Upon IL-1 stimulation MyD88 was recruited to IL-1R1 and endocytosed into endosomes together with Rac-1 and NOX2 in a caveolin-dependent manner. H 2 O 2 produced in this complex facilitated TNFR-associated factor (TRAF6) association with the receptor complex, thereby building a redox-active signaling platform that was called redoxosome (354) (Fig. 13).…”

“…IKKb and IKKe phosphorylate p65 at Ser468, which supports nuclear import (316), whereas phosphorylation by GSK3b rather inhibited the activity of p65 (53). More recently, Ser468-phosphorylated p65 has been shown to be preferentially ubiquitinated and degraded in the nucleus, leading to the termination of NF-jB-dependent gene (354). After docking of IL-1 to IL-1R1 MyD88 is recruited as effector, and initiates endosome formation.…”