SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model

Harraz, Maged M.; Marden, Jennifer J.; Zhou, Weihong; Zhang, Yulong; Williams, Ann E.; Sharov, Victor S.; Nelson, Kathryn; Luo, Meihui; Paulson, Henry L.; Schöneich, Christian; Engelhardt, John F.

doi:10.1172/jci34060

Cited by 228 publications

(353 citation statements)

References 58 publications

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“…Harraz and colleagues [7] have previously shown that wild type SOD1 and mutants L8Q and G10V (both lacking their catalytic activity) bind and activate Rac1, our data suggest that this also occurs for the G93A and G147S mutants. In line with the possibility that also these SOD1 mutants bind and activate Rac1, the similar increase in lamellipodia found in cells overexpressing G93A and G147S is not surprising.…”

Section: Discussionsupporting

confidence: 76%

“…This study is based on data in literature reporting that wild type SOD1 and some ALS-mutated SOD1 forms bind and stabilise the Rho GTPases Rac1 [7]. In glial cells, the authors identified NOX2 as a target of Rac1 activity promoted by SOD1.…”

Section: Discussionmentioning

confidence: 99%

“…Toxicity of mutant SOD1 has been associated with overactivation of NADPH oxidase (NOX2), due to an apparent higher affinity of mutants to the Rac1 member of the Rho GTPase family, compared to the wild-type (WT) SOD1, which in turn would lock NOX2 in its active superoxide-producing form even in oxidising conditions when the WT form dissociates from Rac1 [7]. …”

Section: Introductionmentioning

confidence: 99%

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SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

Ferrari

Verpelli

Crespi

et al. 2018

Communicative & Integrative Biology

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We here investigated the effects of overexpressed superoxide dismutase (SOD)1 and amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants G93A and G147S in Neuro 2A (N2A) cell lines, and found a three-fold increase in lamellipodia either in cells cultured under differentiated or undifferentiated growth conditions. In undifferentiated N2A cells, SOD1 constructs promoted lamellipodial protrusions to similar extent as the overexpression of Rac1, and SOD1-mediated lamellipodia were prevented by coexpression of the N17 dominant-negative form of Rac1, or shRNA for a downstream effector of Rac1, the insulin receptor tyrosine kinase substrate p53 (IRSp53) or its binding partner LIN7. Moreover, no additive effect was measured by coexpression of the SOD1 constructs with Rac1, IRSp53 or LIN7. Collectively these data support a role for SOD1 in the regulation of Rac1-mediated lamellipodia pathway, a property fully retained by the two SOD1 mutants.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

Ferrari

Verpelli

Crespi

et al. 2018

Communicative & Integrative Biology

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“…The common finding of SOD1 recruitment to both TNF-a-and IL-1b-activated redoxosomes also suggests that SOD1 may play an active role in O 2 -dismutation at the surface of the endosome. Such SOD1 functions may be important for mediating localized H 2 O 2 -directed signaling events and=or the redoxsensitive control of Rac1-regulated Nox complexes, as recently described (19).…”

Section: Discussionmentioning

confidence: 81%

Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

Spencer

Oakley

et al. 2009

Antioxidants & Redox Signaling

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110

133

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Growing evidence suggests that NADPH oxidase (Nox)-derived reactive oxygen species (ROS) play important roles in regulating cytokine signaling. We have explored how TNF-a induction of Nox-dependent ROS influences NF-kB activation. Cellular stimulation by TNF-a induced NADPH-dependent superoxide production in the endosomal compartment, and this ROS was required for IKK-mediated activation of NF-kB. Inhibiting endocytosis reduced the ability of TNF-a to induce both NADPH-dependent endosomal superoxide and NF-kB, supporting the notion that redox-dependent signaling of the receptor occurs in the endosome. Molecular analyses demonstrated that endosomal H 2 O 2 was critical for the recruitment of TRAF2 to the TNFR1=TRADD complex after endocytosis. Studies using both Nox2 siRNA and Nox2-knockout primary fibroblasts indicated that Nox2 was critical for TNF-a-mediated induction of endosomal superoxide. Redox-active endosomes that form after TNF-a or IL-1b induction recruit several common proteins (Rac1, Nox2, p67 phox , SOD1), while also retaining specificity for ligand-activated receptor effectors. Our studies suggest that TNF-a and IL-1b signaling pathways both can use Nox2 to facilitate redox activation of their respective receptors at the endosomal level by promoting the redox-dependent recruitment of TRAFs. These studies help to explain how cellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane.

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“…Interaction of WT SOD1 with two casein kinases has been recently reported in the context of a signaling cascade that controls cellular respiration (41). There is also a report that WT SOD1 can bind directly to Rac1 and affect its activity (42). However, whether the misfolded state could mediate either such association is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

Song

Nagy

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mutant human Cu/Zn superoxide dismutase 1 (SOD1) is associated with motor neuron toxicity and death in an inherited form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease). One aspect of toxicity in motor neurons involves diminished fast axonal transport, observed both in transgenic mice and, more recently, in axoplasm isolated from squid giant axons. The latter effect appears to be directly mediated by misfolded SOD1, whose addition activates phosphorylation of p38 MAPK and phosphorylation of kinesin. Here, we observe that several different oligomeric states of a fusion protein, comprising ALS-associated human G85R SOD1 joined with yellow fluorescent protein (G85R SOD1YFP), which produces ALS in transgenic mice, inhibited anterograde transport when added to squid axoplasm. Inhibition was blocked both by an apoptosis signal-regulating kinase 1 (ASK1; MAPKKK) inhibitor and by a p38 inhibitor, indicating the transport defect is mediated through the MAPK cascade. In further incubations, we observed that addition of the mammalian molecular chaperone Hsc70, abundantly associated with G85R SOD1YFP in spinal cord of transgenic mice, exerted partial correction of the transport defect, associated with diminished phosphorylation of p38. Most striking, the addition of the molecular chaperone Hsp110, in a concentration substoichiometric to the mutant SOD1 protein, completely rescued both the transport defect and the phosphorylation of p38. Hsp110 has been demonstrated to act as a nucleotide exchange factor for Hsc70 and, more recently, to be able to cooperate with it to mediate protein disaggregation. We speculate that it can cooperate with endogenous squid Hsp(c)70 to mediate binding and/or disaggregation of mutant SOD1 protein, abrogating toxicity.

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SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model

Cited by 228 publications

References 58 publications

SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

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