RESEARCH

BACKGROUND

Proper functional balance of the cellular proteome is vital for all living cells. Ribosomes in eukaryotic cells produce thousands of different proteins as per requirement (protein synthesis). To perform their functions, newly synthesized proteins must fold into defined 3-dimensional structures (protein folding), maintain this folding state, and move to their destination (protein localization).

Molecular chaperones and other factors aid in these processes. Once their function is over, the proteins are removed by proteasome or autophagy (protein degradation) to replenish the amino acid pool. Protein quality control (PQC) systems coordinately monitor all these events in a form of a network (proteostasis network or PN) to protect the proteome. Protein homeostasis or proteostasis refers to the maintenance of the proteome in the correct conformation, concentration, and location required for its correct function. Proper functional balance of the cellular proteome is absolutely critical for cellular and organismal health.

Failure to maintain the proteome in a functional state leads to proteotoxicity, which is a common feature of many age-related diseases. Indeed, proteostasis capacity tends to decline with aging, leading to an increase in protein misfolding and aggregation. While protein aggregation has been thought to drive pathogenesis, recent evidence suggest that the smaller misfolded and soluble oligomers are the main cause of proteotoxicity. On the other hand, larger aggregates and inclusions are thought to be cytoprotective. This suggests that protein aggregation may not be always detrimental and may be part of cellular defense.

Proteome wide aggregation occurs during stress and aging. Typically stress induced protein aggregation can be resolved once the stress has abated. However, the fate of protein aggregation that occurs during aging is difficult to anticipate, which raises a few important questions:

Is it possible to halt and/or reverse this aggregation?
If yes, how does this influence aging or a healthy lifespan?
How proteotoxicity in one tissue is recognized by distant tissues?
What are the molecular mechanisms that are involved in communicating the stress and priming a stress response?
How does protein quality control work in extracellular space?

We would like to answer these questions using C. elegans as model system with the following objectives.

PROTECTIVE AND REVERSIBLE PROTEIN AGGREGATION

Protein aggregates are considered to be inherently irreversible aberrant clumps and are often associated with pathologies. However, recent evidence demonstrates that protein aggregation can also be an active, organized process. The controlled sequestration of aggregated proteins represents the second line of defense against proteotoxic stress, which is suggested to have protective functions. We have recently shown that small heat shock proteins (small HSPs) play an active role in this process. However, their mechanisms of action particularly during aging remain poorly understood.

How do animals protect their proteome during stress and aging?
Roles for small HSPs in reversible and protective proteome aggregation.

INTER-TISSUE COMMUNICATION AND CELL RESPONSE

In multicellular organisms, proteotoxic stress in one tissue is communicated to distant tissues to maintain proteome integrity for organismal stress resistance and survival. Recently neuronal and non-neuronal tissue communications were implicated in orchestrating systemic stress responses and organism-wide proteostasis. However, the molecular mechanisms and nature of the signaling pathways that integrate this information and promote systemic stress response remain obscure.

How proteotoxic stress in one tissue is communicated with distant tissues?

EXTRACELLULAR PROTEOSTASIS

Mechanisms governing intracellular proteostasis are well described. However, extracellular proteostasis and its maintenance are poorly understood. It is remained to be explored, how the proteins in the extracellular fluid maintain their soluble states and activity. C. elegans offers easy ways to study extracellular proteostasis and can complement studies on mammalian inter-tissue communication.

Importance of extracellular proteostasis in maintaining organism-wide proteostasis.

NOVEL MODIFIERS OF PROTEIN AGGREGATION AND REGULATORS OF LIFESPAN

During stress conditions, young and healthy cells efficiently manage their proteome imbalance by sequestering and depositing misfolded proteins as protein aggregation or inclusions. It is assumed that these aggregate deposits or inclusions contain factors that are required to reverse the protein aggregation (“disaggregases”) under optimal conditions to restore proteome balance. It has been observed that response to proteotoxicity varies among different tissues during stress and aging suggesting the existence of tissue-specific modulators of proteostasis. The identity of such disaggregases in higher eukaryotes remains unclear and if identified can lead to novel therapeutic strategies.

Identification of novel regulators of protein aggregation and lifespan.