The influenza A virus matrix protein 2 undergoes retrograde transport from the endoplasmic reticulum into the cytoplasm and bypasses cytoplasmic proteasomal degradation

Abstract

The matrix protein 2 (M2) is a spliced product of segment 7 genome of influenza A virus. Previous studies indicate its role in uncoating of the viral ribonucleoprotein complex during viral entry and in membrane scission while budding. Despite its crucial role in the viral life cycle, little is known about its subcellular distribution and dynamics. In this study, we have shown that the M2 protein is translocated from the membrane to the cytoplasm by a retrograde route via endosomes and the Golgi network. It utilizes retromer cargo while moving from the endosome to the trans-Golgi network and prevents endosome fusion with the lysosome. Further, M2 interacts with the endoplasmic-reticulum-resident AAA-ATPase p97 for its release into the cytoplasm. Our study also revealed that the M2 protein in the cellular milieu does not undergo ubiquitin-mediated proteasomal degradation. The migration of M2 through this pathway inside the infected cell suggests possible new roles that the M2 protein may have in the host cytoplasm, apart from its previously described functions.

Synthesis of novel derivatives of 7,8‐dihydro‐6H‐imidazo[2,1‐b][1,3]benzothiazol‐5‐one and their virus‐inhibiting activity against influenza A virus

“…We conclude therefore that despite relatively high anti‐viral activity of thiophene‐containing imidazo[2,1‐ b ]thiazole derivatives, they are targeted against neither neuraminidase nor M2 proton channel and have therefore other mechanism of action. This confirms indirectly our initial suggestion that their activity could be based on either inhibition of activity of influenza virus’ polymerase complex or inhibition of membrane‐linked processes in the viral cycle, like transport of RNPs to specific sites of plasma membrane or processes associated with membranes of Golgi complex . Their further optimization may result in development of novel antivirals that are active against drug‐resistant variants of influenza virus.…”

To degrade or not to degrade: mechanisms and significance of endocytic recycling

“…Given their ancient origin and conservation it is perhaps unsurprising that the core cargo retrieval and recycling machinery is targeted by a variety of viral 53, [219][220][221][222][223][224] and bacterial pathogens [225][226][227][228][229][230] , a number of which express proteins that mimic sorting motifs of the host. These pathogens subvert the function of cargo retrieval machineries to promote their intracellular survival and replication.…”

The AAA+ ATPase p97, a cellular multitool

“…Just like with many other cellular processes, viral proteins have evolved to take advantage of and hijack p97 function. The influenza A matrix protein M2 undergoes retrotranslocation from the ER lumen to the cytosol [ 79 ]. This transport mechanism of M2, which does not rely on M2 ubiquitination, is reliant on the ATPase activity of p97 [ 79 ].…”

“…The influenza A matrix protein M2 undergoes retrotranslocation from the ER lumen to the cytosol [ 79 ]. This transport mechanism of M2, which does not rely on M2 ubiquitination, is reliant on the ATPase activity of p97 [ 79 ]. Hepatitis E virus protein ORF2 is another viral protein that relies on p97 to be transported from the ER into the cytosol [ 80 ].…”