Identification of PTPσ as an autophagic phosphatase

Martin, Katie R.; Xu, Yong; Looyenga, Brendan D.; Davis, Ryan J.; Wu, Chia Lun; Tremblay, Michel L.; Xu, Haiyang; MacKeigan, Jeffrey P.

doi:10.1242/jcs.080341

Cited by 55 publications

(36 citation statements)

References 41 publications

(46 reference statements)

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“…39 Indeed, phosphatases have recently been linked to the autophagy pathway, such as several well-known phosphatases (PTEN, PPM1D/WIP1, PTPRS/PTPs, and PPP2CA), and newly identified phosphatases (PGAM5, SGPP1 [sphingosine-1-phosphate phosphatase 1] and calcineurin). 20,[40][41][42][43] However, none of these studies have directly linked the activity of phosphatases to ATG16L1 function. This study not only identified PPP1 as a phosphatase that directly dephosphorylates CSNK2-phosphorylated ATG16Ll, but also indicated that ATG16Ll binds to PPP1 Experiments were repeated at least 3 times.…”

Section: Discussionmentioning

confidence: 99%

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Song¹,

Wang³

et al. 2015

Autophagy

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(2015) ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation, Autophagy, 11:8, 1308-1325, DOI: 10.1080/15548627.2015 Keywords: ATG16L1, autophagy, cardiomyocyte, casein kinase 2, protein phosphatase 1 Abbreviations: ACTB, actinb; AMPK, AMP activated protein kinase; ATG, autophagy-related; BCL2, B-cell CLL/lymphoma 2; BECN1/Beclin 1, autophagy related; CD, Crohn disease; CSNK2, casein kinase 2; GFP, green fluorescent protein; GNB2L1/ RACK1, guanine nucleotide binding protein (G protein)bpolypeptide 2-like 1; GST, glutathione S-transferase; H/R, hypoxia/reoxygenation; I/R, ischemia/reperfusion; LAD, left anterior descending; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; mRFP, monomeric red fluorescent protein; MTORC1, mechanistic target of rapamycin complex 1; NRVCs, neonatal rat ventricular cardiomyocytes; OA, okadaic acid; PE, phosphatidylethanolamine; PPP1, protein phosphatase 1; PPP2, protein phosphatase 2; PVDF, polyvinylidenedifluoride; SNP, single nucleotide polymorphism; SUPT20H/p38IP, suppressor of Ty 20 homolog (S. cerevisiae); TBB, 4,5,6,7-tetrabromobenzotriazole; lPP, l protein phosphatase.Recent studies have shown that the phosphorylation and dephosphorylation of ULK1 and ATG13 are related to autophagy activity. Although ATG16L1 is absolutely required for autophagy induction by affecting the formation of autophagosomes, the post-translational modification of ATG16L1 remains elusive. Here, we explored the regulatory mechanism and role of ATG16L1 phosphorylation for autophagy induction in cardiomyocytes. We showed that ATG16L1 was a phosphoprotein, because phosphorylation of ATG16L1 was detected in rat cardiomyocytes during hypoxia/ reoxygenation (H/R). We not only demonstrated that CSNK2 (casein kinase 2) phosphorylated ATG16L1, but also identified the highly conserved Ser139 as the critical phosphorylation residue for CSNK2. We further established that ATG16L1 associated with the ATG12-ATG5 complex in a Ser139 phosphorylation-dependent manner. In agreement with this finding, CSNK2 inhibitor disrupted the ATG12-ATG5-ATG16L1 complex. Importantly, phosphorylation of ATG16L1 on Ser139 was responsible for H/R-induced autophagy in cardiomyocytes, which protects cardiomyocytes from apoptosis. Conversely, we determined that wild-type PPP1 (protein phosphatase 1), but not the inactive mutant, associated with ATG16L1 and antagonized CSNK2-mediated phosphorylation of ATG16L1. Interestingly, one RVxF consensus site for PPP1 binding in the C-terminal tail of ATG16L1 was identified; mutation of this site disrupted its association with ATG16L1. Notably, CSNK2 also associated with PPP1, but ATG16L1 depletion impaired the interaction between CSNK2 and PPP1. Collectively, these data identify ATG16L1 as a bona fide physiological CSNK2 and PPP1 substrate, which reveals a novel molecular link from CSNK2 to activation of the autophagy-specific ATG12-ATG5-ATG16L1 complex and autoph...

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Section: Discussionmentioning

confidence: 99%

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Song¹,

Wang³

et al. 2015

Autophagy

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“…Functional inactivation of Jumpy [35], and in later work of MTMR3 [36], results in enhancement of basal and stimulated autophagy, indicating that formation and consumption of PtdIns3P are tightly coupled under normal autophagic induction. More recently, the dualdomain PTPσ (protein tyrosine phosphatase σ ) was also shown to negatively regulate autophagy via consumption of the PtdIns3P signal [37].…”

Section: Evidence That Ptdins3p Regulates Autophagosome Formationmentioning

confidence: 99%

How phosphoinositide 3-phosphate controls growth downstream of amino acids and autophagy downstream of amino acid withdrawal

Ktistakis

Manifava

Schoenfelder

et al. 2012

Biochemical Society Transactions

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The simple phosphoinositide PtdIns3P has been shown to control cell growth downstream of amino acid signalling and autophagy downstream of amino acid withdrawal. These opposing effects depend in part on the existence of distinct complexes of Vps34 (vacuolar protein sorting 34), the kinase responsible for the majority of PtdIns3P synthesis in cells: one complex is activated after amino acid withdrawal to induce autophagy and another regulates mTORC1 (mammalian target of rapamycin complex 1) activation when amino acids are present. However, lipid-dependent signalling almost always exhibits a spatial dimension, related to the site of formation of the lipid signal. In the case of PtdIns3P-regulated autophagy induction, recent data suggest that PtdIns3P accumulates in a membrane compartment dynamically connected to the endoplasmic reticulum that constitutes a platform for the formation of some autophagosomes. For PtdIns3P-regulated mTORC1 activity, a spatial context is not yet known: several possibilities can be envisaged based on the known effects of PtdIns3P on the endocytic system and on recent data suggesting that activation of mTORC1 depends on its localization on lysosomes.

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“…98 In contrast, the PtdIns3P phosphatase MTMR14/Jumpy (myotubularin related protein 14), and PTPRD/PTPs (protein tyrosine phosphatase, receptor type, D) act as negative regulators of autophagy by dephosphorylating PtdIns3P or inhibiting PtdIns3P expression in C. elegans and/or mammalian cells. [99][100][101][102] In addition, depletion of PtdIns3P phosphatases MTMR6 and MTMR7 increase LC3-II in mammalian cells suggesting they are also negative regulators of autophagy, although the mechanism is unknown. 100 These findings suggest that phosphorylation/ dephosphorylation of PtdIns3P can either positively or negatively regulate autophagic initiation depending on the PtdIns3P kinases and phosphatases involved.…”

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confidence: 99%

Posttranslational modification of autophagy-related proteins in macroautophagy

Xie¹,

et al. 2014

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Macroautophagy is an intracellular catabolic process involved in the formation of multiple membrane structures ranging from phagophores to autophagosomes and autolysosomes. Dysfunction of macroautophagy is implicated in both physiological and pathological conditions. To date, 38 autophagy-related (ATG) genes have been identified as controlling these complicated membrane dynamics during macroautophagy in yeast; approximately half of these genes are clearly conserved up to human, and there are additional genes whose products function in autophagy in higher eukaryotes that are not found in yeast. The function of the ATG proteins, in particular their ability to interact with a number of macroautophagic regulators, is modulated by posttranslational modifications (PTMs) such as phosphorylation, glycosylation, ubiquitination, acetylation, lipidation, and proteolysis. In this review, we summarize our current knowledge of the role of ATG protein PTMs and their functional relevance in macroautophagy. Unraveling how these PTMs regulate ATG protein function during macroautophagy will not only reveal fundamental mechanistic insights into the regulatory process, but also provide new therapeutic targets for the treatment of autophagy-associated diseases.

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Identification of PTPσ as an autophagic phosphatase

Cited by 55 publications

References 41 publications

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

How phosphoinositide 3-phosphate controls growth downstream of amino acids and autophagy downstream of amino acid withdrawal

Posttranslational modification of autophagy-related proteins in macroautophagy

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