Functional and pathological relevance of HERC family proteins: a decade later

Abstract

The HERC gene family encodes proteins with two characteristic domains in their sequence: the HECT domain and the RCC1-like domain (RLD). In humans, the HERC family comprises six members that can be divided into two groups based on their molecular mass and domain structure. Whereas large HERCs (HERC1 and HERC2) contain one HECT and more than one RLD, small HERCs (HERC3-6) possess single HECT and RLD domains. Accumulating evidence shows the HERC family proteins to be key components of a wide range of cellular functions, including neurodevelopment, DNA damage repair, cell growth and immune response. Considering the significant recent advances made regarding HERC functionality, an updated review summarizing the progress is greatly needed at 10 years since the last HERC review. We provide an integrated view of HERC function and go into detail about its implications for several human diseases such as cancer and neurological disorders.

Keywords: HECT; HERC proteins; RCC1; RLD; Ubiquitin ligase.

Fig. 1

Structure of HERC proteins. The RCC1-like domains (RLDs), HECT domain and several other conserved regions are indicated. Schema of the structures of RCC1 and HECT characterized by a seven-bladed β-propeller fold and a bilobed shape, respectively. The HECT domain provides the ability to act as an ubiquitin/ubiquitin-like (UBL) protein ligase. Ubiquitin/UBL proteins are conjugated to target proteins via a hierarchical cascade composed of an E1 activating enzyme, an E2 conjugating enzyme and an E3 ligase. An E3 ligase containing a HECT domain forms a thioester bond with ubiquitin/UBL proteins via its active cysteine residue (Cys: in the bilobed structure) and once the conjugate has been formed, ubiquitin/UBL is transferred to the target’s lysine residue. U ubiquitin/UBL protein, SPRY spl A and RyR, BH3 Bcl-2 homology domain 3, WD40 G protein β-subunit like repeats, Cyt b5 cytochrome b5-like region, M-H mind-bomb/HERC2 domain, CPH conserved domain within Cullin 7 (Cul7), Parkin-like cytoplasmic (PARC) and HERC2, ZZ ZZ-type zinc finger, DOC domain homologous to subunit 10 of the anaphase promoting complex (APC)

Fig. 2

Expression of HERC proteins. a mRNA expression in human tissues using RNA sequencing. Expression values are shown in reads per kilobase of transcript per million mapped reads (RPKM). Data available from GTExPortal. b Subcellular localization of HERC proteins

Fig. 3

Schematic drawing showing HERC2 interactors and the cellular functions involved. HERC2 functions as a modulator of centrosomes through its association with neuralized homologue 4 (NEURL4) and ubiquitin specific peptidase 33 (USP33). HERC2 regulates F-box and leucine-rich repeat protein 5 (FBXL5), a subunit of the SCF ubiquitin ligase complex which targets iron regulatory protein 2 (IRP2) for proteasomal degradation. In turn, IRP2 regulates at the posttranscriptional level proteins that contribute to iron homeostasis such as ferritin. An intracellular iron excess promotes nuclear receptor coactivator 4 (NCOA4) ubiquitination by HERC2, reducing the autophagic turnover of ferritin. A complex formed by leucine-rich repeat kinase 2 (LRRK2), NEURL4 and HERC2 stimulates endocytosis and recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl). HERC2 stimulates p53 oligomerization and activates its transcriptional activity. HERC2 tightly controls genomic stability through the regulation of proteins such as xeroderma pigmetosum A (XPA), breast cancer 1 (BRCA1), tumor suppressor candidate 4 (TUSC4), RING finger protein 8 (RNF8), RING finger protein 168 (RNF168), Claspin and the deubiquitinases USP16 and USP20