Abstract
The catalytically inactive mitogen-activated protein (MAP) kinase phosphatase, MK-STYX (MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosine-binding protein) interacts with the stress granule nucleator G3BP-1 (Ras-GAP (GTPase-activating protein) SH3 (Src homology 3) domain-binding protein-1), and decreases stress granule (stalled mRNA) formation. Histone deacetylase isoform 6 (HDAC6) also binds G3BP-1 and serves as a major component of stress granules. The discovery that MK-STYX and HDAC6 both interact with G3BP-1 led us to investigate the effects of MK-STYX on HDAC6 dynamics. In control HEK/293 cells, HDAC6 was cytosolic, as expected, and formed aggregates under conditions of stress. In contrast, in cells overexpressing MK-STYX, HDAC6 was both nuclear and cytosolic and the number of stress-induced aggregates significantly decreased. Immunoblots showed that MK-STYX decreases HDAC6 serine phosphorylation, protein tyrosine phosphorylation, and lysine acetylation. HDAC6 is known to regulate microtubule dynamics to form aggregates. MK-STYX did not affect the organization of microtubules, but did affect their post-translational modification. Tubulin acetylation was increased in the presence of MK-STYX. In addition, the detyrosination of tubulin was significantly increased in the presence of MK-STYX. These findings show that MK-STYX decreases the number of HDAC6-containing aggregates and alters their localization, sustains microtubule acetylation, and increases detyrosination of microtubules, implicating MK-STYX as a signaling molecule in HDAC6 activity.
Highlights
MK-STYX (MAPK phosphoserine/threonine/tyrosine-binding protein) is a catalytically inactive member of the protein tyrosine phosphatase (PTP) superfamily, classified as a pseudophosphatase [1,2,3,4]
Because acetylation of Histone deacetylase isoform 6 (HDAC6) is important for HDAC6 function [25,38], we examined whether MK-STYX alters acetylation
The shared function of MK-STYX and HDAC6 as regulators in the stress granule life cycle led to investigating whether MK-STYX has a role in HDAC6 dynamics
Summary
MK-STYX (MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosine-binding protein) is a catalytically inactive member of the protein tyrosine phosphatase (PTP) superfamily, classified as a pseudophosphatase [1,2,3,4]. MK-STYX plays an important regulatory role in a number of cellular pathways, including apoptosis, neurite formation, and stress granule assembly [3,4,5,6,7,8,9,10]. MK-STYX binds G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1) [3,4,10], a nucleator of stress granules [11], thereby inhibiting stress granule formation. The inhibitory effects of MK-STYX are independent of the phosphorylation status of G3BP-1 at Ser149, the critical residue that regulates its activity as a stress granule nucleator [4,10,11]
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