Research Groups

RNP granules and cross-talk with the protein quality control machinery

Stress-inducible RNP granules form as a response to external stress and are associated with the protein quality control (PQC) machinery. How do these RNP granules form and dissolve and what is the role of the PQC machinery in this process? We analyzed P bodies (PB) and stress granules (SG) in budding yeast and found that they have distinct material properties. Whereas PBs behave as liquid droplets, SGs adopt a solid material state, which is reminiscent of protein aggregates (Kroschwald et al., 2015) (Figure 1). We found that ATP-consuming disaggregases are critical for the maintenance of the liquid-like PB state as well as for the dissolution of solid SGs. We could further show that RNP granule assembly pathways are highly redundant. Importantly, assembly often involves promiscuous interactions between prion-like domains and misfolded proteins. 

Although mammalian SGs show more liquid-like material properties than yeast SGs, they also show highly promiscuous behavior with increasing stress. Misfolding-prone proteins accumulate in SGs during severe stress, thus recruiting PQC machinery and impairing SG functionality (Mateju et al., in preparation). These studies reveal RNP granules as a weak link in cellular biology, which, owing to their conformational promiscuity and metastable liquid-like properties, promote the development of aging-associated diseases.

<b>Figure 1.</b> Molecular mechanisms underlying the formation of stress-inducible RNP granules. Stress-inducible RNP granules have different compositions, which affect their dynamic and material properties. The presumed average interaction strength is indicated in red. The amyloid state on the left is an aberrant state that is associated with disease. PLD: prion-like domain; RBD: RNA-binding domain; SD: An aggregation-prone stress sensor domain.

Future Plans:

Our primary goal is to study the phase behavior of several RNP granule-associated proteins and RNAs in vitro. Relying on such in vitro experiments and using a recently established assay for the ectopic nucleation of RNP granules in vivo, we aim to uncover important principles of compartment formation. Additional studies will investigate the role of ATP-driven machines such as disaggregases and helicases in regulating compartment formation. Finally, we will investigate the question of why misfolded proteins selectively accumulate in stress-inducible RNP granules. This will allow us to identify important triggers that lead on a pathway to aging-associated cellular decline.