E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1 (By similarity). Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair (By similarity). Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4 (PubMed:7478539). Ubiquitinates MFN2 to negatively regulate mitochondrial fusion in response to decreased stearoylation of TFRC (By similarity). Ubiquitination of MFN2 also takes place following induction of mitophagy; AMBRA1 acts as a cofactor for HUWE1-mediated ubiquitination (By similarity). Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN (By similarity). May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation (By similarity). Mediates polyubiquitination of PA2G4 (By similarity). Acts in concert with MYCBP2 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquination and degradation of NR1D1 (By similarity). Binds to an upstream initiator-like sequence in the preprodynorphin gene (PubMed:7968380). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Protein modification; protein ubiquitination. Interacts with isoform p14ARF of CDKN2A which strongly inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN, POLB and CDC6. Interacts with isoform 2 of PA2G4. Interacts with NR1D1. Interacts with AMBRA1 (By similarity). Mainly expressed in the cytoplasm of most tissues, except in the nucleus of spermatogonia, primary spermatocytes and neuronal cells (By similarity). Recruited to mitochondria following interaction with AMBRA1 (By similarity). Widely expressed. During spermatogenesis highest expression at postnatal day 10 and then gradually decreases to day 40, after which it remains constant at low levels. Protein peaks at postnatal day 20, and then gradually decreases by day 45. The HECT domain mediates inhibition of the transcriptional activity of p53. Phosphorylated on tyrosine, phosphorylation is probably required for its ability to inhibit TP53 transactivation.