Sis1 potentiates the stress response to protein aggregation and elevated temperature

Area of Science:

• Cellular Biology
• Molecular Biology
• Stress Response Mechanisms

Background:

• Cells activate stress responses to maintain protein conformational stability.
• Mechanisms for sensing misfolded proteins and inducing productive stress responses are not fully understood.
• Disease-associated protein aggregates can evade effective cellular stress responses.

Purpose of the Study:

• To identify the key mechanisms cells use to sense proteotoxic stress.
• To elucidate the role of Sis1 in managing protein misfolding and aggregation.
• To investigate the conserved function of Sis1 and its mammalian homolog, DnaJB6, in stress response regulation.

Main Methods:

• Utilized a yeast model of polyQ protein aggregation.
• Investigated the function of Sis1 (Hsp40 co-chaperone) and Hsp70.
• Examined the impact of Sis1 levels on polyQ aggregate formation and cellular stress response.

Main Results:

• Sis1 was identified as a critical sensor of proteotoxic stress.
• Elevated Sis1 levels prevented dense polyQ inclusions and promoted permeable condensates.
• Sis1 facilitated Hsp70 accumulation, leading to potent HSF1-dependent stress response activation.
• Sis1/DnaJB6 demonstrated a conserved role in regulating the cellular heat stress response magnitude.

Conclusions:

• Sis1/DnaJB6 acts as a limiting regulator in sensing protein misfolding and orchestrating cellular stress responses.
• This function enables a dynamic stress response, preventing hypersensitivity to environmental changes.
• The findings reveal a conserved mechanism for sensing and responding to proteotoxic stress across species.