rDNA Condensation Promotes rDNA Separation from Nucleolar Proteins Degraded for Nucleophagy after TORC1 Inactivation

Abstract

Graphical Abstract Highlights d TORC1 inactivation-induced rDNA condensation promotes rDNA repositioning d Condensin, Rpd3-Sin3, and Hmo1 promote the rDNA repositioning d These factors are required for nucleophagic degradation of nucleolar proteins In Brief Nutrient starvation and TORC1 inactivation induce the repositioning of rDNA and nucleolar proteins and nucleophagic degradation of nucleolar proteins in budding yeast. Mostofa et al. report that condensin, Rpd3 HDAC, and Hmo1 promote rDNA condensation, as well as the repositioning and nucleophagic degradation of nucleolar proteins. SUMMARYNutrient starvation and inactivation of target of rapamycin complex 1 (TORC1) protein kinase induce nucleophagy preferentially degrading only nucleolar components in budding yeast. Nucleolar proteins are relocated to sites proximal to the nucleus-vacuole junction (NVJ), where micronucleophagy occurs, whereas rDNA, which is embedded in the nucleolus under normal conditions, moves to NVJ-distal regions, causing rDNA dissociation from nucleolar proteins after TORC1 inactivation. This repositioning is mediated via chromosome linkage INM protein (CLIP)-cohibin complexes that tether rDNA to the inner nuclear membrane. Here, we show that TORC1 inactivation-induced rDNA condensation promotes the repositioning of rDNA and nucleolar proteins. Defects in condensin, Rpd3-Sin3 histone deacetylase (HDAC), and high-mobility group protein 1 (Hmo1), which are involved in TORC1 inactivationinduced rDNA condensation, compromised the repositioning and nucleophagic degradation of nucleolar proteins, although rDNA still escaped from nucleophagic degradation in these mutants. We propose a model in which rDNA condensation after TORC1 inactivation generates a motive force for the repositioning of rDNA and nucleolar proteins.

Microautophagy – distinct molecular mechanisms handle cargoes of many sizes

“…Micronucleophagy selectively occurs at the NVJ. In addition, it preferentially targets the nucleolus, but spares nucleolus-embedded rDNA, and thus has sub-organellar specificity (Mostofa et al, 2019).…”

Nucleophagy—Implications for Microautophagy and Health

“…DNA, specifically rDNA, is separated from the nucleolus and condensed in the initial stages of nucleophagy, allowing for degradation of nucleolar proteins while retaining rDNA. rDNA exclusion from nucleophagic cargo is mediated by two mechanisms, the CLIP cohibin system that retracts rDNA to the INM and condensation of rDNA [ 55 , 59 , 60 , 61 ]. DNA damage induces autophagy in yeast by a process termed genotoxin-induced targeted autophagy (GTA) and defective autophagy inhibits DNA repair.…”

Nuclear ingression of cytoplasmic bodies accompanies a boost in autophagy

“…Helped by additional factors, such as Snd3 (Tosal-Castano et al, 2021), the NVJ expands "zipper-wise" during nutritional stress, such as glucose and amino acid shortage, and upon target of rapamycin complex (TORC) inhibition (Hariri et al, 2018). This increase in the contact surface can serve to send esterified lipids for storage within lipid droplets (Hariri et al, 2018), to increase the flux of metabolites through the mevalonate pathway (Rogers et al, 2021), to modulate the sphingolipid biosynthetic pathway (Kvam & Goldfarb, 2006;Henne et al, 2015), or to recycle nonessential nuclear components (Kvam & Goldfarb, 2007), such as nucleolar proteins and forming ribosomes, as to decrease the cell's translation capacity (Kvam & Goldfarb, 2007;Mostofa et al, 2018;Mostofa et al, 2019). Furthermore, the NVJ is important to alleviate stress associated to defective nuclear pore complex assembly (Lord & Wente, 2020).…”