CONICET | Buscador de Institutos y Recursos Humanos

&lt;!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";} p.MsoBodyText, li.MsoBodyText, div.MsoBodyText {mso-style-link:"Body Text Char"; margin:0in; margin-bottom:.0001pt; line-height:200%; mso-pagination:widow-orphan; text-autospace:none; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman"; mso-fareast-language:ES; font-weight:bold;} span.BodyTextChar {mso-style-name:"Body Text Char"; mso-style-locked:yes; mso-style-link:"Body Text"; mso-ansi-font-size:12.0pt; mso-bidi-font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:"Times New Roman"; mso-hansi-font-family:"Times New Roman"; mso-ansi-language:EN-US; font-weight:bold;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --&gt;  The transcriptional response to hypoxia is mediated by a transcription factor termed Hypoxia Inducible Factor (HIF) that regulates the expression of a wide array of hypoxia inducible genes. It has been characterized as a a/b heterodimer of basic-helix-loop-helix-PAS (bHLH-PAS) proteins in which the b-subunit is constitutive and the a-subunit is regulated by oxygen through different mechanisms that include control of protein half-life, recruitment of transcriptional co-activators, and regulation of subcellular localization. Work from our group and other laboratories has led to the definition of a hypoxia inducible transcriptional response in Drosophila that is homologous to that of mammalian HIF, in which Drosophila Tango (Tgo) and Similar (Sima) are the HIFb and HIFa homologues respectively. Whereas Tgo (HIFb) is not regulated by oxygen, Sima (HIFa) protein is stabilized in hypoxia, degradation being dependent on a key prolyl residue that is hydroxylated by a HIF prolyl-4-hydroxylase, which we have named Fatiga. We have conducted a genome-wide RNAi screen in S2 cells at the Drosophila RNAi Screening Center at Harvard Medical School, to identify genes required for HIF activation. After 3 rounds of selection, 35 genes emerged as critical HIF regulators in hypoxia, 22 of which had not been previously associated to HIF biology. A gene that we have named Zonda (Zda) emerged from the screen as a positive regulator of HIF. To gain insights into Zonda/FKBP38 cellular function, we began by studying its subcellular localization. We generated transgenic lines expressing Zda-GFP and Zda-Cherry fusion constructs, and performed co-localization analyses in fat body cells of 3rd instar larvae using available fluorescent markers of various subcellular compartments. Zda exhibited an even distribution in cells of fed larvae, and after a 4 h of starvation period, formed discrete foci that co-localized with the autophagosome marker ATG8-GFP. This striking colocalization redirected our efforts to the study of Zda as a possible regulator of autophagy. Further experiments suggested that Zda plays a central role in autophagy: Zda overexpression is sufficient to induce autophagy, as detected by the aggregation of ATG8-cherry and the accumulation of the lysosome marker lysotracker in fat body cells of well-fed larvae. Moreover, Zda is absolutely required for autophagy, since zda null mutant cells fail to induce autophagy, as assessed by ATG8-cherry and lysotracker nucleation under starvation conditions. The autophagy cascade and the TOR pathway have opposite effects on cell or organismal growth. Taking into account the domain similarities between Zda and FKBP38, and that FKBP38 was proposed to be a negative regulator of mTOR, we hypothesized that Zda may behave as a growth inhibitor.