Angiomotin-Like 1 Links Paramyxovirus M Proteins to NEDD4 Family Ubiquitin Ligases

Abstract

To define the links between paramyxovirus budding and cellular ESCRT machinery, we previously identified angiomotin-like 1 (AMOTL1) in a screen for host factors that bind to the matrix (M) protein of parainfluenza virus 5 (PIV5). This protein harbors three L/PPXY sequences, allowing it to interact with WW domain containing proteins including NEDD4 family members. We hypothesize that paramyxoviruses use AMOTL1 as a linker to indirectly recruit the same NEDD4 ubiquitin ligases for budding that other enveloped viruses recruit directly through their PPXY late domains. In support of this hypothesis, we found that AMOTL1 could link together M proteins and NEDD4 family proteins in three-way co-IP experiments. Both PIV5 and mumps virus M proteins could be linked to the NEDD4 family proteins NEDD4-1, NEDD4L, and NEDL1, provided that AMOTL1 was co-expressed as a bridging protein. AMOT and AMOTL2 could not substitute for AMOTL1, as they lacked the ability to bind with paramyxovirus M proteins. Attachment of a PPXY late domain sequence to PIV5 M protein obviated the need for AMOTL1 as a linker between M and NEDD4 proteins. Together, these results suggest a novel host factor recruitment strategy for paramyxoviruses to achieve particle release.

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

“…One of the key regulators of YAP1 localization and activity is Amot, which binds strongly to the first WW-domain of YAP1 via one of its multiple N-terminal PPxY motifs [84]. Amot, along with other family members, plays an important role in the biology of the vascular system, and Amot has been linked previously to budding of other RNA viruses [85][86][87][88]. Interestingly, we observed a dose-dependent rescue of mVP40 VLP budding when increasing amounts of Amot were added to cells co-expressing mVP40 and either YAP1 or TAZ.…”

Chicken bromodomain-containing protein 2 interacts with the Newcastle disease virus matrix protein and promotes viral replication

“…Regarding paramyxovirus M protein and host protein interactions, it has been reported that the interaction of the Nipah and Hendra virus M proteins with AP3B1 protein promotes virus-like particle (VLP) production [ 33 ]. In addition, the angiomotin-like 1 protein interacts with the parainfluenza virus 5 (PIV5) M protein [ 34 ] and acts as a linker between the PIV5 M and NEDD4 ubiquitin ligases [ 35 ], which reveals a novel host factor recruitment strategy for paramyxoviruses to achieve VLP production and virus budding. Moreover, a recent study showed that annexin A2 interacting with the measles virus (MeV) M protein mediates the plasma membrane localization of the M protein and assists the assembly and budding of progeny virions [ 36 ].…”

The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

“…This neatly explains why NEDD4-2, which binds to PPXY that HIV lacks, rescues the late domain mutant lacking both PTAP and YPXL domains [ 103 ]. AMOT-1 was also shown to facilitate paramyxovirus budding in a similar manner as it does in HIV [ 108 , 109 ]. However, AMOT-1 (but not the other members of the agiomotin family) is specifically required for bridging the M protein and E3 ubiquitin ligase [ 109 ].…”