SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Protein aggregates accumulate in aggresomes at the microtubule organizing center (MTOC) for degradation by autophagy.
• Histone deacetylase 6 (HDAC6) and sequestosome 1 (p62) are implicated in aggresome formation and autophagic clearance.
• HDAC6 activity is crucial for aggresome formation and can be modulated by protein interactions.

Purpose of the Study:

• To investigate the direct interaction between p62 and HDAC6.
• To determine if this interaction affects HDAC6 activity and cortactin-F-actin assembly.
• To elucidate the role of p62 in regulating HDAC6-mediated cellular functions.

Main Methods:

• Protein interaction mapping to identify and characterize the direct binding between HDAC6 and p62.
• Biochemical assays to assess HDAC6 deacetylase activity in the presence and absence of p62.
• Cellular imaging to observe the localization and function of cortactin-F-actin assemblies under different conditions.

Main Results:

• A direct interaction between HDAC6 and p62 was identified and mapped.
• The p62-HDAC6 interaction regulates HDAC6 deacetylase activity.
• Absence of p62 leads to HDAC6 hyperactivation, deacetylation of α-tubulin and cortactin, and impaired perinuclear co-localization of cortactin-F-actin assemblies.

Conclusions:

• p62 plays a critical role in regulating HDAC6 activity.
• p62 is essential for recruiting F-actin networks to the MTOC for autophagic clearance of protein aggregates.
• The p62-HDAC6 interaction is a key regulatory mechanism in the cellular response to protein aggregation.