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Essential Genetic Interactors of SIR2 Required for Spatial Sequestration and Asymmetrical Inheritance of Protein Aggregates

J. Song ; Q. Yang ; Junsheng Yang ; Lisa C Larsson ; Xinxin Hao ; Xuefeng Zhu ; Sandra Malmgren Hill ; Marija Cvijovic (Institutionen för matematiska vetenskaper) ; Julia Fernandez-Rodriguez ; Julie Grantham ; Claes M Gustafsson ; Beidong Liu ; Thomas Nyström
PLoS Genetics (1553-7390). Vol. 10 (2014), 7, p. Article Number: e1004539 .
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: STRUCTURED ILLUMINATION MICROSCOPY, YEAST ACTIN CYTOSKELETON, SACCHAROMYCES-CEREVISIAE, BUDDING YEAST, DAMAGED PROTEINS, ENDOPLASMIC-RETICULUM, INTERACTION NETWORK, MISFOLDED PROTEINS, QUALITY-CONTROL, LIFE-SPAN, Genetics & Heredity



Denna post skapades 2014-09-08. Senast ändrad 2015-02-04.
CPL Pubid: 202472

 

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Institutioner (Chalmers)

Institutionen för kemi och molekylärbiologi (GU)
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi (GU)
Institutionen för matematiska vetenskaperInstitutionen för matematiska vetenskaper (GU)
Core Facilities, Centre for Cellular Imaging (GU)

Ämnesområden

Medicinsk genetik
Mikrobiologi inom det medicinska området

Chalmers infrastruktur

 


Projekt

Denna publikation är ett resultat av följande projekt:


Spatial protein quality control and its links to aging, proteotoxicity, and polarity (QUALIAGE) (EC/FP7/268630)