Biology subjects

Lartey, D.

Publications and source records attributed to Lartey, D..

3 recordsLinked to original sources

bioRxiv2025

Design principles of a membrane-spanning ubiquitin ligase

Receptor-type E3 ubiquitin ligases are membrane-spanning assemblies that enable extracellular signals to directly control ubiquitylation in the cytoplasm. Despite playing widespread roles in tissue patterning and homeostasis, metabolism, and immunity, their structures and mechanisms remain poorly understood. Using cryo-electron microscopy, integrated with biophysical and functional studies, we visualized an E3 complex composed of two transmembrane proteins, MEGF8 and MOSMO, and the intracellular RING-family protein MGRN1. This MEGF8-MOSMO-MGRN1 (MMM) complex regulates left-right patterning of the body axis and the development of multiple organs, partly by attenuating signaling through the Hedgehog pathway. We find that the MMM complex functions like a fishing pole: a long, flexible helix attached to a membrane platform suspends an activated and precisely oriented RING domain--like a fishhook--to ubiquitylate the cytoplasmic surfaces of target receptors. Our structure explains how mutations in MEGF8 cause multi-organ birth defects in humans and defines a paradigm for receptor regulation by ubiquitylation.

biochemistry↗

bioRxiv2025

The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters

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.

cell biology↗

bioRxiv2024

Identification of an Outbreak of Bivalve Transmissible Neoplasia in Soft-Shell Clams (Mya arenaria) in the Puget Sound Using Hemolymph and eDNA Surveys

Bivalve transmissible neoplasia (BTN) is one of three known types of naturally transmissible cancer-- cancers in which the whole cancer cells move from individual to individual, spreading through natural populations. BTN is a lethal leukemia-like cancer that has been observed throughout soft-shell clam (Mya arenaria) populations on the east coast of North America, with two distinct sublineages circulating at low enzootic levels in New England, USA, and Prince Edward Island, Canada. Major cancer outbreaks likely due to Mya arenaria BTN (MarBTN) were reported in 1980s and the 2000s and the disease has been observed since the 1970s, but it has not been observed in populations of this clam species on the US west coast. In 2022, we collected soft-shell clams from several sites in Puget Sound, Washington, USA, and unexpectedly found high prevalence of BTN in two sites (Triangle Cove on Camano Island and near Stanwood in South Skagit Bay). Prevalence of BTN increased in subsequent years, reaching >75% in both sites in 2024, while it was not observed in other sites, suggesting the early stages of a severe disease outbreak following recent introduction. We observed that these cancer cells contain several somatic transposing insertion sites found only in the USA-sublineage of MarBTN, showing that it likely was recently transplanted from New England to this location. We then developed a sensitive environmental DNA (eDNA) assay, using qPCR to target somatic mutations in the MarBTN mitogenome, and showed that MarBTN can be detected in seawater at Triangle Cove, as well as several kilometers outside of the cove. We then used this assay to survey 50 sites throughout Puget Sound, confirming that the disease can be detected at high levels at Triangle Cove and South Skagit Bay, and showing that it extends beyond these known sites. However, while normal soft-shell clam mtDNA was widely detected, MarBTN was undetectable throughout most of Puget Sound and currently remains limited to the South Skagit Bay area and north Port Susan. These results identify a previously unknown severe outbreak of a transmissible cancer due to long-distance transplantation of disease from another ocean, and they demonstrate the utility of eDNA methods to track the spread of BTN through the environment.

ecology↗