The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1864; no. 10; pp. 1844 - 1854
• Main Authors: Zanchetta, Melania E., Napolitano, Luisa M.R., Maddalo, Danilo, Meroni, Germana
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2017
• Subjects: Amino Acid Sequence; BRAF35; Cleft Palate - genetics; Cleft Palate - pathology; Cytoplasm - enzymology; Esophagus - abnormalities; Esophagus - pathology; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - pathology; High Mobility Group Proteins - genetics; Humans; Hypertelorism - genetics; Hypertelorism - pathology; Hypospadias - genetics; Hypospadias - pathology; Microtubule Proteins - genetics; Microtubule Proteins - metabolism; MID1; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Opitz G/BBB Syndrome; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; TRIM E3 ligases; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; SPRY; Opitz G/BBB Syndrome; TRIM; PTM; E1; E2; E3; HECT; Ubiquitination; RING; BRAF35; iBRAF/HMG20a; RFP; CC; HMG; RBR; SUMO; OS; FN3; PP2A; MID1; Ub; MID2; BRAF35/HMG20b; XLOS; HMW; TRIM E3 ligases; coREST/RCOR1; RBCC; BHC; HDAC
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.07.014

MID1/TRIM18 is a member of the TRIM family of ubiquitin E3 ligases characterized by the presence of a conserved RING-containing N-terminal tripartite motif. Mutations in the MID1 gene have been associated with the X-linked form of Opitz Syndrome, a developmental disorder characterized by midline defects and intellectual disability. The effect of MID1 E3 ligase activity within the cell and the role in the pathogenesis of the disease is still not completely unraveled. Here, we report BRAF35, a non-canonical HMG nuclear factor, as a novel MID1 substrate. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We observed a partial co-localization of the two proteins within cytoplasmic bodies. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance. Our data reveal a novel role for MID1 and for atypical ubiquitination in balancing BRAF35 presence, and likely its activity, within nuclear and cytoplasmic compartments. •BRAF35/HMG20b is a novel MID1/TRIM18 partner.•BRAF35 is ubiquitinated and its stability is controlled by the proteasome.•MID1 promotes BRAF35 atypical ubiquitination.•MID1 controls BRAF35 cytoplasmic abundance.