Essential Genetic Interactors of SIR2 Required for Spatial Sequestration and Asymmetrical Inheritance of Protein Aggregates
Artikel i vetenskaplig tidskrift, 2014

Sir2 is a central regulator of yeast aging and its deficiency increases daughter cell inheritance of stress-and aging-induced misfolded proteins deposited in aggregates and inclusion bodies. Here, by quantifying traits predicted to affect aggregate inheritance in a passive manner, we found that a passive diffusion model cannot explain Sir2-dependent failures in mother-biased segregation of either the small aggregates formed by the misfolded Huntingtin, Htt103Q, disease protein or heat-induced Hsp104-associated aggregates. Instead, we found that the genetic interaction network of SIR2 comprises specific essential genes required for mother-biased segregation including those encoding components of the actin cytoskeleton, the actin-associated myosin V motor protein Myo2, and the actin organization protein calmodulin, Cmd1. Co-staining with Hsp104-GFP demonstrated that misfolded Htt103Q is sequestered into small aggregates, akin to stress foci formed upon heat stress, that fail to coalesce into inclusion bodies. Importantly, these Htt103Q foci, as well as the ATPase-defective Hsp104(Y662A)-associated structures previously shown to be stable stress foci, co-localized with Cmd1 and Myo2-enriched structures and super-resolution 3-D microscopy demonstrated that they are associated with actin cables. Moreover, we found that Hsp42 is required for formation of heat-induced Hsp104(Y662A) foci but not Htt103Q foci suggesting that the routes employed for foci formation are not identical. In addition to genes involved in actin-dependent processes, SIR2-interactors required for asymmetrical inheritance of Htt103Q and heat-induced aggregates encode essential sec genes involved in ER-to-Golgi trafficking/ER homeostasis.

YEAST ACTIN CYTOSKELETON

QUALITY-CONTROL

MISFOLDED PROTEINS

LIFE-SPAN

ENDOPLASMIC-RETICULUM

STRUCTURED ILLUMINATION MICROSCOPY

SACCHAROMYCES-CEREVISIAE

BUDDING YEAST

DAMAGED PROTEINS

INTERACTION NETWORK

Genetics & Heredity

Författare

J. Song

Harbin Institute of Technology

Q. Yang

Harbin Institute of Technology

Junsheng Yang

Göteborgs universitet

Lisa C Larsson

Göteborgs universitet

Xinxin Hao

Göteborgs universitet

Xuefeng Zhu

Göteborgs universitet

Sandra Malmgren Hill

Göteborgs universitet

Marija Cvijovic

Göteborgs universitet

Chalmers, Matematiska vetenskaper, Matematik

Julia Fernandez-Rodriguez

Göteborgs universitet

Julie Grantham

Göteborgs universitet

Claes M Gustafsson

Göteborgs universitet

Beidong Liu

Göteborgs universitet

Thomas Nyström

Göteborgs universitet

PLoS Genetics

1553-7390 (ISSN) 1553-7404 (eISSN)

Vol. 10 Article Number: e1004539 - e1004539

Ämneskategorier

Medicinsk genetik

Mikrobiologi inom det medicinska området

DOI

10.1371/journal.pgen.1004539