14 15 ¶ These authors equally contributed to this work 16 § Corresponding authors 17 18 occurrence of MN with weak envelopes; conversely, aberrant membrane 40 remodelling at micronuclei generates a steady state pool of cytosolic DNA that 41 may contribute to sustaining pro-inflammatory pathways in cancer cells. 42 43 Keywords 44 Micronuclei, genomic instability, cytosolic DNA, nuclear envelope, ESCRT-III 45 46 Therefore, an intact NE around a micronucleus maintains the integrity of its genetic 61 material 4-6 and thereby protects against chromothripsis. 62 NE integrity at the primary nucleus is ensured by ESCRT-III, a universal membrane-63 remodeling complex. Specifically, ESCRT-III seals nuclear membranes during late 64 mitosis and repairs mechanical rupture of the NE during interphase 7-10 . Core ESCRT-65 III subunits, including the critical membrane-deforming polymer CHMP4B (Charged 66 Multivesicular body Protein 4B), are recruited by CHMP7 11 , a specialized ESCRT-III 67 subunit that is targeted to NE gaps by associating with the chromatin binding 68 protein LEM2(ref.12). ESCRT-III seals these gaps by supporting reverse-topology 69membrane scission 13 . ESCRT-III activity at the NE is short-lived, and is regulated by 70 the AAA ATPase, VPS4. VPS4 remodels ESCRT-III to drive membrane scission, and 71 also recycles ESCRT-III subunits back into the cytosol 13 . 72Loss of micronuclear compartmentalization exposes of DNA to the cytosol, which 73 drives protective immune responses 14 . Cytosolic DNA is recognized as foreign by 74 innate immune pathways involving cyclic GAMP synthase (cGAS) 15 . cGAS binds to 75 specific secondary structures within exposed double and single-stranded DNA and 76 stimulates the production of 2′-5′ cyclic GMP-AMP (cGAMP) 16 . 77Here we present how ESCRT-III protects the genome from the instability generated 78 by micronuclei. We show that ESCRT-III and VPS4 support micronuclear envelope 79 membrane integrity, mirroring their role in maintaining the primary NE 17 . We also 80
Cells respond to alterations in their nutrient environment by adjusting the abundance of surface nutrient transporters and receptors. This can be achieved through modulation of ubiquitin-dependent endocytosis, which in part is regulated by the NEDD4 family of E3 ligases. Here we report four novel modes by which Pub1, a fission yeast Schizosaccharomyces pombe member of the NEDD4-family of E3 ligases, is regulated. Phosphorylation of the conserved serine 188 (an analogous site in human NEDD4L is phosphorylated but uncharacterized) provides resistance to extracellular canavanine, a toxic arginine analog, indicating S188 phosphorylation enhances Pub1 function to reduce canavanine uptake. Both Pub1 serine 188 phosphorylation and proteasomal turnover of Pub1 are inhibited by Gsk3 kinase. Thus, whilst Gsk3 kinase protects Pub1 protein levels it restrains Pub1 E3 ligase function by reducing serine 188 phosphorylation. Nitrogen stress stimulates Pub1 protein turnover by the proteasome, reducing protein levels by 60% and thereby increasing abundance of the amino acid transporter Aat1 at the plasma membrane. TOR complex 2 and Gad8 (AKT) signaling negatively regulates Pub1 protein levels, and the increased proteasomal Pub1 turnover upon nitrogen stress requires TORC2 signaling. In summary, environmental control of Pub1 protein levels to modulate the abundance of nutrient transporters is regulated by the major TORC2 nutrient-sensing signaling network and proteasomal dependent control of Pub1 protein levels.
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