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Conservation and Rewiring of Functional Modules Revealed by an Epistasis Map in Fission Yeast
Roguev, A.,Bandyopadhyay, S.,Zofall, M.,Zhang, K.,Fischer, T.,Collins, S. R.,Qu, H.,Shales, M.,Park, H.-O.,Hayles, J.,Hoe, K.-L.,Kim, D.-U.,Ideker, T.,Grewal, S. I.,Weissman, J. S.,Krogan, N. J. American Association for the Advancement of Scienc 2008 Science Vol.322 No.5900
Yeast SREBP Cleavage Activation Requires the Golgi Dsc E3 Ligase Complex
Stewart, Emerson ,V.,Nwosu, Christine ,C.,Tong, Zongtian,Roguev, Assen,Cummins, Timothy ,D.,Kim, Dong-Uk,Hayles, Jacqueline,Park, Han-Oh,Hoe, Kwang-Lae,Powell, David ,W.,Krogan, Nevan& Elsevier 2011 Molecular cell Vol.42 No.2
<P><B>Summary</B></P><P>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 <I>d</I>efective for <I>S</I>REBP <I>c</I>leavage, <I>dsc1-4</I>, encoding components of a transmembrane Golgi E3 ligase complex with structural homology to the Hrd1 E3 ligase complex involved in endoplasmic reticulum-associated degradation. The Dsc complex binds SREBP and cleavage requires components of the ubiquitin-proteasome pathway: the E2-conjugating enzyme Ubc4, the Dsc1 RING E3 ligase, and the proteasome. <I>dsc</I> mutants display conserved aggravating genetic interactions with components of the multivesicular body pathway in fission yeast and budding yeast, which lacks SREBP. Together, these data suggest that the Golgi Dsc E3 ligase complex functions in a post-ER pathway for protein degradation.</P> <P><B>Graphical Abstract</B></P><P><ce:figure id='dfig1'></ce:figure></P><P><B>Highlights</B></P><P>► Yeast SREBP is proteolytically activated by a different mechanism than mammalian SREBP ► Deletion collection screen identified four <I>dsc</I> genes required for fission yeast SREBP cleavage ► Dsc proteins form a Golgi E3 ligase complex that resembles Hrd1 E3 ligase in ERAD ► Yeast SREBP cleavage requires activities of the ubiquitin-proteasome pathway</P>