Heterochromatin protein 1 (HP1) isoforms are conserved non-histone chromatin-binding proteins that play an important role in packaging of heterochromatin and gene regulation. The functions of HP1 isoforms alpha and beta are influenced by the nuclear lamins. Cells expressing disease-causing lamin A rod domain mutants show depletion of HP1 alpha and beta and E3 ubiquitin ligase HECW2 is upregulated in these cells. However, the role of HECW2 in the turnover of HP1 proteins has been hitherto unexplored. Here, we show that HECW2 interacts with HP1 isoforms alpha and beta but not HP1 gamma. Ectopic expression of HECW2 causes the ubiquitination of HP1 alpha and beta, thereby targeting them for proteasomal degradation. Down regulation of HECW2 increases their steady-state levels indicating its role in their homeostatic regulation. Our results give important insights into the mechanism of proteasomal degradation of HP1 proteins in laminopathic cells. (C) 2018 Elsevier Inc. All rights reserved.