A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes.

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that (inc-finger ranscription actor-11), the sole Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event.

Dsc E3 ligase localization to the Golgi requires the ATPase Cdc48 and cofactor Ufd1 for activation of sterol regulatory element-binding protein in fission yeast.

Sterol regulatory element-binding proteins (SREBPs) in the fission yeast regulate lipid homeostasis and the hypoxic response under conditions of low sterol or oxygen availability. SREBPs are cleaved in the Golgi through the combined action of the Dsc E3 ligase complex, the rhomboid protease Rbd2, and the essential ATPases associated with diverse cellular activities (AAA) ATPase Cdc48. The soluble SREBP N-terminal transcription factor domain is then released into the cytosol to enter the nucleus and regulate gene expression.

Coordinate Regulation of Yeast Sterol Regulatory Element-binding Protein (SREBP) and Mga2 Transcription Factors.

The Mga2 and Sre1 transcription factors regulate oxygen-responsive lipid homeostasis in the fission yeast in a manner analogous to the mammalian sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 transcription factors. Mga2 and SREBP-1 regulate triacylglycerol and glycerophospholipid synthesis, whereas Sre1 and SREBP-2 regulate sterol synthesis. In mammals, a shared activation mechanism allows for coordinate regulation of SREBP-1 and SREBP-2.

Mga2 Transcription Factor Regulates an Oxygen-responsive Lipid Homeostasis Pathway in Fission Yeast.

Eukaryotic lipid synthesis is oxygen-dependent with cholesterol synthesis requiring 11 oxygen molecules and fatty acid desaturation requiring 1 oxygen molecule per double bond. Accordingly, organisms evaluate oxygen availability to control lipid homeostasis. The sterol regulatory element-binding protein (SREBP) transcription factors regulate lipid homeostasis.

Yeast sterol regulatory element-binding protein (SREBP) cleavage requires Cdc48 and Dsc5, a ubiquitin regulatory X domain-containing subunit of the Golgi Dsc E3 ligase.

Schizosaccharomyces pombe Sre1 is a membrane-bound transcription factor that controls adaptation to hypoxia. Like its mammalian homolog, sterol regulatory element-binding protein (SREBP), Sre1 activation requires release from the membrane. However, in fission yeast, this release occurs through a strikingly different mechanism that requires the Golgi Dsc E3 ubiquitin ligase complex and the proteasome.

Yeast SREBP cleavage activation requires the Golgi Dsc E3 ligase complex.

Mammalian lipid homeostasis requires proteolytic activation of membrane-bound sterol regulatory element binding protein (SREBP) transcription factors through sequential action of the Golgi Site-1 and Site-2 proteases. Here we report that while SREBP function is conserved in fungi, fission yeast employs a different mechanism for SREBP cleavage. Using genetics and biochemistry, we identified four genes defective for SREBP cleavage, dsc1-4, encoding components of a transmembrane Golgi E3 ligase complex with structural homology to the Hrd1 E3 ligase complex involved in endoplasmic reticulum-associated degradation.

Oxygen-dependent binding of Nro1 to the prolyl hydroxylase Ofd1 regulates SREBP degradation in yeast.

Sre1, the fission yeast sterol regulatory element-binding protein, is an ER membrane-bound transcription factor that controls adaptation to low oxygen growth. Under low oxygen, Sre1 is proteolytically cleaved and the N-terminal transcription factor domain (Sre1N) is released from the membrane and enters the nucleus to activate hypoxic gene expression. Ofd1, a prolyl 4-hydroxylase-like 2-oxoglutarate dioxygenase, controls the oxygen-dependent stability of Sre1N.

Identification of twenty-three mutations in fission yeast Scap that constitutively activate SREBP.

The endoplasmic reticulum membrane protein SREBP cleavage-activating protein (Scap) senses sterols and regulates activation of sterol-regulatory element binding proteins (SREBPs), membrane-bound transcription factors that control lipid homeostasis in fission yeast and mammals. Transmembrane segments 2-6 of Scap function as a sterol-sensing domain (SSD) that recognizes changes in cellular sterols and facilitates activation of SREBP. Previous studies identified conserved mutations Y298C, L315F, and D443N in the SSD of mammalian Scap and fission yeast Scap (Scp1) that render cells insensitive to sterols and cause constitutive SREBP activation.

Sterol regulatory element binding protein is a principal regulator of anaerobic gene expression in fission yeast.

Fission yeast sterol regulatory element binding protein (SREBP), called Sre1p, functions in an oxygen-sensing pathway to allow adaptation to fluctuating oxygen concentrations. The Sre1p-Scp1p complex responds to oxygen-dependent sterol synthesis as an indirect measure of oxygen availability. To examine the role of Sre1p in anaerobic gene expression in Schizosaccharomyces pombe, we performed transcriptional profiling experiments after a shift to anaerobic conditions for 1.