E3 ubiquitin ligase HECW2 mediates the proteasomal degradation of HP1 isoforms

The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress

“…Dodo stabilizes HP1a in complex with LamB in a phosphorylation-dependent manner Loss of Dodo did not alter HP1a mRNA levels (Figure S4A) but caused HP1a protein degradation because treating dodo mutant or dodo RNAi -expressing fly brains with the proteasome inhibitor MG132 restored HP1a protein to levels similar to the WT (Figures S4B and 4A). In human cells, HP1a degradation has been shown to depend on the E3 ubiquitin ligases HECW2, RNF123, and FBXW10 (Chaturvedi and Parnaik, 2010;Chaturvedi et al, 2012;Krishnamoorthy et al, 2018). In WT fly brains, treatment with the PIN1 catalytic inhibitor KPT6566 (Campaner et al, 2017) was associated with reduction of HP1a protein levels, which was rescued by knockout of Hecw (Figure 4B), the Drosophila ortholog of HECW2 (Fajner et al, 2021).…”

“…In human epithelial cell lines, HP1a protein levels are regulated by Lamin A/C, which inhibits HECW2-dependent HP1a degradation (Chaturvedi and Parnaik, 2010;Chaturvedi et al, 2012;Krishnamoorthy et al, 2018). However, fly brain neurons express LamB and much less Lamin C (LamC) (Lenz-Bö hme et al, 1997), whose further reduction did not alter HP1a protein levels, as (E) Alkaline COMET assay in 4-day-old WT control, dodo EY03779 mutant, and 5-Gy g-irradiated (IR) WT fly brains.…”

How HP1 Post-Translational Modifications Regulate Heterochromatin Formation and Maintenance

“…The ubiquitin ligase RNF123 has also been shown to ubiquitinate and contribute to the degradation of HP1α and HP1β, but not HP1γ, upon lamin A/C mutations [68]. HECW2, another E3 ubiquitin ligase, has also been reported to target HP1α and HP1β for proteasomal degradation [69].…”

HECW2‐related disorder in four Japanese patients

“…On the other hand, screening of HECW2‐interacting proteins identified several lamin‐associated proteins, including lamin B1, prelamin A, emerin, HP1 isoforms, and proliferating cell nuclear antigen (PCNA) as potential substrates for HECW2 (Krishnamoorthy et al, 2018b). Furthermore, the steady‐state levels of HP1 increased through the downregulation of HECW2, indicating that HECW2 may play a role in the turnover of HP1 in normal cycling cells (Krishnamoorthy et al, 2018a). However, it is still unclear whether these quantitative effects of HECW2 are really related to HECW2 ‐related disorder.…”