The Armadillo Repeat-containing Protein, ARMCX3, Physically and Functionally Interacts with the Developmental Regulatory Factor Sox10

Abstract

Sox10 is a member of the group E Sox transcription factor family and plays key roles in neural crest development and subsequent cellular differentiation. Sox10 binds to regulatory sequences in target genes via its conserved high mobility group domain. In most cases, Sox10 exerts its transcriptional effects in concert with other DNA-binding factors, adaptor proteins, and nuclear import proteins. These interactions can lead to synergistic gene activation and can be cell type-specific. In earlier work, we demonstrated that Sox10 transactivates the nicotinic acetylcholine receptor ␣3 and ␤4 subunit genes and does so only in neuronal-like cell lines, raising the possibility that Sox10 mediates its effects via interactions with co-regulatory factors. Here we describe the identification of the armadillo repeat-containing protein, ARMCX3, as a Sox10-interacting protein. Biochemical analyses indicate that ARMCX3 is an integral membrane protein of the mitochondrial outer membrane. Others have shown that Sox10 is a nucleocytoplasmic shuttling protein. We extend this observation and demonstrate that, in the cytoplasm, Sox10 is peripherally associated with the mitochondrial outer membrane. Both Sox10 and ARMCX3 are expressed in mouse brain and spinal cord as well as several cell lines. Overexpression of ARMCX3 increased the amount of mitochondrially associated Sox10. In addition, although ARMCX3 does not possess intrinsic transcriptional activity, it does enhance transactivation of the nicotinic acetylcholine receptor ␣3 and ␤4 subunit gene promoters by Sox10. These results suggest that Sox10 is a membrane-associated factor whose transcriptional function is increased by direct interactions with ARMCX3 and raise the possibility of a signal transduction cascade between the nucleus and mitochondria through Sox10/ARMCX3 interactions.

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

“…Several members, including Alex3, have nuclear localization in neurons. This observation is consistent with a previous study showing interaction of Alex3 with the transcription factor Sox10 and enhancement of its transcriptional activity by Alex3 22 . These observations support that Armcx genes have biological functions in two compartments (namely, mitochondria and nucleus), as has been shown for other proteins, including Sox10, DISC1 and HDAC1 [39][40][41] .…”

“…2e,f). These observations are consistent with a previous study reporting Alex3 protein in outer membrane mitochondrial fractions 22 .…”

“…These observations support that Armcx genes have biological functions in two compartments (namely, mitochondria and nucleus), as has been shown for other proteins, including Sox10, DISC1 and HDAC1 [39][40][41] . Finally, because of their transcriptional control 22 and the presence of six Arm domains, Armcx/Arm10 genes may functionally interact with the Wnt/β-catenin pathway. The observation that the lack of the N-terminal region targets Alex3 to the nucleus and the existence of a putative starting codon at the first internal methionine (aa 38) raise the possibility of alternatively translated isoforms acting selectively at the mitochondria or in the nucleus.…”

ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

“…Though the classical ARM family was involved in a variety of processes such as cell adhesion, embryogenesis and tumorigenesis (Peifer et al, 1994;Hatzfeld, 1999), little is known about the ALEX genes. Recent report demonstrates that the ALEX3 directly interacts with the sex determining region Y (Sry)-box 10 (SOX10) transcription factor via the ARM repeat domains and alters its subcellular localization and transcriptional activity (Mou et al, 2009). In addition, the study have shown that the ALEX3 gene encodes a mitochondrial-targeted protein and the non-canonical Wnt/PKC pathway regulates mitochondrial distribution through ALEX3 protein degradation (Serrat et al, 2013).…”

Expression and tissue distribution of human X-linked armadillo repeat containing-6

“…their amino (n)-terminal region harbors a transmembrane domain, suggesting that these proteins may localize at membrane structures in cells. recently, armcx3 was revealed as an integral membrane protein of the mitochondrial outer membrane that functionally interacts with the transcriptional regulator Sox10 (4). in addition, ARMCX4, ARMCX5 and ARMCX6, the localizations of which have been mapped to chromosome regions xq22.1, xq22.1-q22.3 and Xq21.33-q22.3, respectively, were also identified.…”