An actin-WHAMM interaction linking SETD2 and autophagy

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• Autophagy, a cellular degradation process, is frequently dysregulated in clear cell renal cell carcinoma (ccRCC).
• The histone methyltransferase SETD2 is often inactivated in ccRCC and plays a role in regulating cytoskeletal proteins, including actin.
• SETD2's methylation of actin at lysine 68 (ActK68me3) influences actin polymerization dynamics, a process crucial for cellular functions like autophagy.

Purpose of the Study:

• To investigate the role of SETD2 inactivation in autophagy defects observed in ccRCC.
• To determine the impact of SETD2 loss on the interaction between actin cytoskeleton regulators and actin.
• To elucidate the mechanism by which SETD2 deficiency affects autophagy initiation.

Main Methods:

• Analysis of autophagy defects in SETD2-deficient cells.
• Assessment of the interaction between the actin nucleation promoting factor WHAMM and actin.
• Pharmacological manipulation of actin polymerization using Jasplakinolide in SETD2-null cells.

Main Results:

• SETD2-null cells exhibit significant autophagy defects.
• A decreased interaction between WHAMM and actin was observed in SETD2-deficient cells, hindering autophagy initiation.
• Pharmacological induction of actin polymerization rescued the WHAMM-actin binding deficit and restored autophagy in SETD2-null cells.

Conclusions:

• The autophagy defects in SETD2-null cells are primarily due to altered actin dynamics, not the loss of the specific ActK68me3 mark.
• Functional impairment of actin polymerization is critical for the observed autophagy deficits in SETD2-deficient ccRCC.
• Targeting actin dynamics presents a potential therapeutic strategy for ccRCC with SETD2 inactivation.