An actin-WHAMM interaction linking SETD2 and autophagy

Biochem Biophys Res Commun. 2021 Jun 18:558:202-208. doi: 10.1016/j.bbrc.2020.09.025. Epub 2020 Oct 6.

Abstract

The process of autophagy is dysregulated in many cancers including clear cell renal cell carcinoma (ccRCC). Autophagy involves the coordination of numerous autophagy-related (ATG) genes, as well as processes involving the actin cytoskeleton. The histone methyltransferase SETD2, frequently inactivated in ccRCC, has recently been shown to also methylate cytoskeletal proteins, which in the case of actin lysine 68 trimethylation (ActK68me3) regulates actin polymerization dynamics. Here we show that cells lacking SETD2 exhibit autophagy defects, as well as decreased interaction of the actin nucleation promoting factor WHAMM with its target actin, which is required for initiation of autophagy. Interestingly, the WHAMM actin binding deficit could be rescued with pharmacologic induction of actin polymerization in SETD2-null cells using Jasplakinolide. These data indicate that the decreased interaction between WHAMM and its target actin in SETD2-null cells was secondary to altered actin dynamics rather than loss of the SETD2 ActK68me3 mark itself, and underscores the importance of the functional defect in actin polymerization in SETD2-null cells exhibiting autophagy defects.

Keywords: Actin; Autophagy; Renal cell carcinoma; SETD2; WHAMM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism*
  • Autophagy / genetics
  • Autophagy / physiology
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line
  • Cell Line, Tumor
  • Down-Regulation
  • Gene Knockout Techniques
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / metabolism*

Substances

  • Actins
  • Autophagy-Related Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • WHAMM protein, human
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human