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.

HERC4 Is Overexpressed in Hepatocellular Carcinoma and Contributes to the Proliferation and Migration of Hepatocellular Carcinoma Cells

“…In addition, HERC4 also functions in tumor tissues. HERC4 highly expresses both in lung cancer (Sanchez-Tena et al, 2016) and breast cancer (Deng et al, 2010), and is closely related to clinic pathological parameters, suggesting that HERC4 is likely to be a diagnostic biomarker for lung cancer and breast cancer. Besides, HERC4 interacts with transcription factor c-Maf and catalyzed its polyubiquitination and subsequent proteasomemediated degradation, leading to inhibition of multiple myeloma proliferation (Hochrainer et al, 2008).…”

“…HERC2 interacts with the coiled-coil domain of USP16 through its C-terminal HECT domain (Sanchez-Tena et al, 2016). In response to DNA damage, HERC2 knockdown affects the levels of ubiquitinated H2A through the action of USP16 (Zhang et al, 2014).…”

A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

“…HERC1 belongs to the class 1 family of HECT E3 ubiquitin ligases, which also includes HERC2 and the small HERC proteins, and which usually contain a SPRY domain (Grau-Bove et al, 2013;Scheffner and Kumar, 2014). Although HECT E3 ubiquitin ligases appear to regulate many physiological processes, including membrane receptor and transporter trafficking, mTOR signalling, and transcription or chromatin remodelling, the exact function of HERC1 and HERC2 remain unclear (Sanchez-Tena et al, 2016;Rotin and Kumar, 2009;Garcia-Gonzalo and Rosa, 2005). The HECT domain of HERC1 has been shown to conjugate ubiquitin through its active site cysteine, indicating that it is very likely a functional ubiquitin ligase, but no clear substrates have been identified so far (Sanchez-Tena et al, 2016).…”

“…Although HECT E3 ubiquitin ligases appear to regulate many physiological processes, including membrane receptor and transporter trafficking, mTOR signalling, and transcription or chromatin remodelling, the exact function of HERC1 and HERC2 remain unclear (Sanchez-Tena et al, 2016;Rotin and Kumar, 2009;Garcia-Gonzalo and Rosa, 2005). The HECT domain of HERC1 has been shown to conjugate ubiquitin through its active site cysteine, indicating that it is very likely a functional ubiquitin ligase, but no clear substrates have been identified so far (Sanchez-Tena et al, 2016). HERC2 has been shown to regulate the stability of several proteins involved in DNA damage repair.…”

A short evolutionary journey across the HERC Ubiquitin Ligases

“…The HERC members are proteins of different size (ranging from 100-120 kDa to >500 kDa), characterized by the presence of two conserved domains: I) a catalytic HECT domain localized at their C-terminus and II) one or more (up to three) RCC1-like domain (RLD) 8 . HECT is a domain of ~350 amino acids firstly described in Human Papilloma Virus (HPV) E6-Associated Protein (E6AP).…”