The Microtubule-associated Histone Deacetylase 6 (HDAC6) Regulates Epidermal Growth Factor Receptor (EGFR) Endocytic Trafficking and Degradation

Abstract

Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with tubulin deacetylase activity, and it binds dynein motors. Recent studies revealed that microtubule acetylation affects the affinity and processivity of microtubule motors. These unique properties implicate a role for HDAC6 in intracellular organelle transport. Here, we show that HDAC6 associates with the endosomal compartments and controls epidermal growth factor receptor (EGFR) trafficking and degradation. We found that loss of HDAC6 promoted EGFR degradation. Mechanistically, HDAC6 deficiency did not cause aberrant EGFR internalization and recycling. Rather, it resulted in accelerated segregation of EGFR from early endosomes and premature delivery of EGFR to the late endosomal and lysosomal compartments. The deregulated EGFR endocytic trafficking was accompanied by an increase in microtubule-dependent movement of EGFR-bearing vesicles, revealing a novel regulation of EGFR vesicular trafficking and degradation by the microtubule deacetylase HDAC6.Endocytosis and subsequent delivery of endosomal cargos to lysosomes are essential for the degradation of many membrane-associated proteins that are critical for cell signaling. This process is crucial for determination of the amplitude of growth factor signaling and is therefore tightly regulated. In this aspect, the complete itinerary starting from the cell surface to the degradative lysosomes near the cell center has been illustrated using the epidermal growth factor (EGF) 2 -activated EGFR as a model system. Activated EGF receptors are first internalized through clathrin-dependent endocytosis. The receptors are then either sorted into the recycling endosomes and return to the cytoplasmic membrane, or are centripetally transported from the early endosomes to the multivesicular bodies (MVBs)/late endosomes before they are dumped into lysosomes for degradation. The lysosomal degradation of EGFR has been identified as a key mechanism to attenuate the EGF signaling. Deregulation of this pathway has been linked to the development and progression of varied types of human cancers (reviewed in Ref. 1). Despite the fact that much effort has been invested in the research of EGFR endocytosis and its intracellular transport, the transition of EGFR from early to late endosomes is still not well understood. Earlier lines of evidence suggest that sorting and transport of early endocytic cargos to later stage endocytic compartments require microtubules and microtubule-associated motors (2-6). However, how microtubules and post-translational modifications on tubulin, especially tubulin acetylation (7), regulate EGFR intracellular trafficking has not been completely elucidated.Unlike other histone deacetylases with chromatin remodeling activity, HDAC6 catalyzes deacetylation of cytoplasmic substrates, such as ␣-tubulin, Hsp90, and cortactin (8 -11). In HDAC6-deficient cells, the entire microtubule network becomes hyperacetylated (8,12). Unexpectedly, ␣-tubulin acetylation alone does not affect microtubule-depe...

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“…Gao et and controls EGFR trafficking and degradation (10). This is consistent with data from Deribe et al showing that HDAC6 negatively regulates EGFR endocytosis and degradation by controlling the acetylation status of α-tubulin and subsequently receptor trafficking along microtubules (11).…”

Monoubiquitination of Filamin B Regulates Vascular Endothelial Growth Factor-Mediated Trafficking of Histone Deacetylase 7

“…In vitro deacetylation assays also demonstrated that class IIa HDACs possess potent deacetylase activity (31). Recently, we along with other labs have demonstrated that class IIa HDACs, including HDAC4 and HDAC7, are able to potentiate sumoylation of a variety of proteins including PML, LXR, MEF2, and HIC1 (19,25,(32)(33)(34). In this study, we show for the first time that HDAC7 binds FLNB in a ubiquitination-dependent manner.…”

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“…Class IIB includes HDAC6 and HDAC10. HDAC6 is a major cytoplasmic protein deacetylase whose substrates include a-tubulin and heat shock protein 90 (HSP90); it also plays a role in diverse cellular functions such as aggresome formation and epidermal growth factor receptor signaling, independent of deacetylase activity (87,124,141,154). Comparatively little is known about HDAC10 and its role in transcriptional regulation.…”