Mahogunin ring finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitylation and degradation. Although MGRN1 is known to reg Show more
Mahogunin ring finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitylation and degradation. Although MGRN1 is known to regulate the Hedgehog signaling effector Smoothened (SMO) via the transmembrane adapter multiple epidermal growth factor-like 8 (MEGF8), the broader scope of its regulatory network has been speculative. Here, we identify attractin (ATRN) and attractin-like 1 (ATRNL1) as additional transmembrane adapters that recruit MGRN1 and regulate cell surface receptor turnover. Through co-immunoprecipitation, we show that ATRN interacts with the RING domain of MGRN1. Functional assays suggest that ATRN and ATRNL1 work with MGRN1 to promote the ubiquitylation and degradation of the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 or ATRN leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, resulting in enhanced eumelanin production. These findings expand the known repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to facilitate substrate receptor specificity. Show less
E3 ubiquitin ligases play a crucial role in modulating receptor stability and signaling at the cell surface, yet the mechanisms governing their substrate specificity remain incompletely understood. Ma Show more
E3 ubiquitin ligases play a crucial role in modulating receptor stability and signaling at the cell surface, yet the mechanisms governing their substrate specificity remain incompletely understood. Mahogunin Ring Finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitination and degradation. Unlike cytosolic E3 ligases, membrane-tethered E3s require transmembrane adapters to selectively recognize and regulate surface receptors, yet few such ligases have been studied in detail. While MGRN1 is known to regulate the receptor Smoothened (SMO) within the Hedgehog pathway through its interaction with the transmembrane adapter Multiple Epidermal Growth Factor-like 8 (MEGF8), the broader scope of its regulatory network has been speculative. Here, we identify Attractin (ATRN) and Attractin-like 1 (ATRNL1) as additional transmembrane adapters that recruit MGRN1 and regulate cell surface receptor turnover. Through co-immunoprecipitation, we show that ATRN and ATRNL1 likely interact with the RING domain of MGRN1. Functional assays reveal that MGRN1 requires these transmembrane adapters to ubiquitinate and degrade the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, with the latter resulting in enhanced eumelanin production. These findings expand the repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to dictate substrate receptor specificity. By elucidating how MGRN1 selectively engages with surface receptors, this work establishes a broader framework for understanding how this unique class of E3 ligases fine-tunes receptor homeostasis and signaling output. Show less