A Nedd4 E3 Ubiquitin Ligase Pathway Inhibits Robo1 Repulsion and Promotes Commissural Axon Guidance across the Midline

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

“…In addition, single and double conditional knockouts of Nedd4-1 and Nedd4-2 display impaired axon guidance across the floor plate of the spinal cord. Taken together, these findings demonstrate an important role for mammalian Nedd4 homologs in commissural axon guidance in the spinal cord (Gorla et al, 2022). The finding that some Nedd4 family members do not facilitate Robo1 ubiquitination and degradation despite binding effectively to Ndfip proteins suggests that additional factors are required to confer substrate specificity to E3 ligases.…”

“…These additional factors appear to be highly cell-type specific, as the same cargo can be ubiquitinated by different E3 ligases in different cellular contexts. For example, Ndfip-mediated ubiquitylation of the divalent metal ion transporter (DMT1) is catalyzed by Nedd4-2 in neuronal cells (Howitt et al, 2009), but is catalyzed by WWP2 in other non-neuronal cell types (Foot et al, 2008; Gorla et al, 2022). .…”

“…These additional factors appear to be highly cell-type specific, as the same cargo can be ubiquitinated by different E3 ligases in different cellular contexts. For example, Ndfipmediated ubiquitylation of the divalent metal ion transporter (DMT1) is catalyzed by Nedd4-2 in neuronal cells (Howitt et al, 2009), but is catalyzed by WWP2 in other non-neuronal cell types (Foot et al, 2008;Gorla et al, 2022) Discovering additional binding partners for both Comm and Ndfip proteins, especially those shared between both, will be necessary for us to better understand other critical players in this common mechanism. Such binding partners may include proteins involved in determining E3 substrate specificity and in trafficking Nedd4 adaptors and their cargoes to the proper destinations.…”

Molecular encoding of stimulus features in a single sensory neuron type enables neuronal and behavioral plasticity

“…PY motif containing proteins can be direct targets of protein degradation by the Nedd4 family of E3 ubiquitin ligases via interaction with their WW domains (Rotin et al, 2001; Harty et al, 2000). A subset of small PY-containing transmembrane proteins that otherwise do not share extensive sequence homology have also been shown to act as adapters to recruit these ligases to target proteins that may themselves lack the PY motif (Myat et al, 2002; Hettema et al, 2004; Gorla et al, 2022). However, the levels of the endogenously tagged GCY-18 guanylyl cyclase was unaltered in pyt-1 mutant animals after a shift from 15°C to 25°C for 4 hrs (Figure S5C), suggesting that PYT-modulates cGMP levels at the AFD thermosensory endings via alternative mechanisms.…”

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

“…These additional factors appear to be highly cell-type specific, as the same cargo can be ubiquitinated by different E3 ligases in different cellular contexts. For example, Ndfip-mediated ubiquitylation of the divalent metal ion transporter (DMT1) is catalyzed by Nedd4-2 in neuronal cells (Howitt et al, 2009 ), but is catalyzed by WWP2 in other non-neuronal cell types (Foot et al, 2008 ;Gorla et al, 2022 ).. What factors may determine E3 ligase substrate specificity in the developing mammalian and insect CNS remains an open question.…”