Role for DUSP1 (dual-specificity protein phosphatase 1) in the regulation of autophagy

Abstract

Accumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy. Specifically, we demonstrate that DUSP1 knockdown by shRNA in human ovarian cancer CAOV3 cells and knockout in murine embryonic fibroblasts, increases both basal and rapamycin-increased autophagic flux. Overexpression of DUSP1 had the opposite effect. Importantly, knockout of Dusp1 promoted phosphorylation of ULK1 at Ser555, and BECN1/Beclin 1 at Ser15, and the association of PIK3C3/VPS34, ATG14, BECN1 and MAPK, leading to the activation of the autophagosome-initiating class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Furthermore, knockdown and pharmacological inhibitor studies indicated that DUSP1-mediated suppression of autophagy reflected inactivation of the MAPK1-MAPK3 members of the MAPK family. Knockdown of DUSP1 sensitized CAOV3 cells to rapamycin-induced antigrowth activity. Moreover, CAOV3-CR cells, a line that had acquired cisplatin resistance, exhibited an elevated DUSP1 level and were refractory to rapamycin-induced autophagy and cytostatic effects. Knockdown of DUSP1 in CAOV3-CR cells restored sensitivity to rapamycin. Collectively, this work identifies a previously unrecognized role for DUSP1 in regulating autophagy and suggests that suppression of DUSP1 may enhance the therapeutic activity of rapamycin.

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

“…Recently, MKP has been suggested to regulate autophagy [ 26 ]. To further explore whether MKP-5 would regulate apoptosis and dysfunction by autophagy pathway, Rin-PC and Rin-MKP-5 cells were treated with both PA and with the autophagic inhibitor 3-MA for 9h.…”

“…Conversely, another study has suggested that MKP-4 negatively regulates insulin signaling, potentially thereby contributing to the pathogenesis of insulin resistance [ 25 ]. In addition, increasing evidence indicates that MKPs can regulate autophagy in the context of MKP-1 knockdown via increasing both basal and rapamycin-induced autophagic flux [ 26 ]. Recently, one study has indicated that MKP-5 limits reactive oxygen species (ROS) production and can prevent lipopolysaccharide (LPS) -induced vascular injury in mice [ 27 ].…”

Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases

“…Knockdown of DUSP1 leads to induction of autophagy in ERK-dependent manner as observed in ovarian cancer cells. DUSP1 knockdown probably mediates this effect via reduced dephosphorylation of ULK and increased LC3II formation which then results in autophagosome formation and maturation [ 137 ]. DUSP1 may also dephosphorylate the scaffolding protein, JIP1, to maintain retrograde transport of autophagosomes in axons, thus allowing them to mature and help in protein clearance [ 138 ].…”

Alterations in mitochondrial fission, fusion, and mitophagic protein expression in the gastrocnemius of mice after a sciatic nerve transection

“…The reduction in activated AMPK over the course of 35 days did not prevent elevations in ULK1 phosphorylation on AMPK‐specific sites. This may be due to reduced posttranslational modifications such as ubiquitination and proteosomal degradation of ULK1 or reduced phosphatase activity . The reduction in AMPK phosphorylation has been noted before in paralyzed muscle following 7 days of denervation as well as in individuals 1 year after SCI .…”

“…This may be due to reduced posttranslational modifications such as ubiquitination and proteosomal degradation of ULK1 21 or reduced phosphatase activity. 22 The reduction in AMPK phosphorylation has been noted before in paralyzed muscle following 7 days of denervation 23 as well as in individuals 1 year after SCI. 24 Conversely, AMPK activity has been shown to remain unchanged in rat soleus and gastrocnemius after 3 days of denervation 25 and after 10 weeks in the rat soleus after SCI.…”