Meta-Biol

• Pathways

Viral RNP, bound by M1 and NEP/NS2 interacting with CRM1, are shuttled through the nuclear pore into the cytoplasm (Martin, 1991; O'Neill, 1998; Buolo, 2006). This mechanism may resemble export of HIV-1 ribonucleoprotein, where the HIV-1 Rev export protein interacts with CRM1 (Askjaer, 1998). A number of cofactors are implicated in CRM1-mediated export, including the small GTPase Ran, Ran-binding proteins 1 and 3, and a guanine nucleotide exchange factor (Nilsson, 2001; Nemergut, 2002; Petosa, 2004). Ternary CRM1-cofactor-cargo complexes likely interact transiently with nuclear pore proteins (nucleoporins) as they traverse the pore (reviewed in Suntharalingam, 2003). RanGTP is hydrolyzed to RanGDP in the cytoplasm, an activity that can be stimulated by NEP/NS2 (Akarsu, 2003). Influenza infection activates Raf/MEK/ERK signaling, which is necessary for NEP/NS2-mediated export of viral RNP (Pleschka, 2001; Marjuki, 2006). Influenza vRNP complexes released into the cytoplasm do not re-enter the nucleus, as they are thought to remain bound by M1, preventing re-import (Martin, 1991). It has been suggested that M1 binding of zinc cations could distinguish M1 bound to the vRNP from polymerized, matrix M1 present in nascent virions (Elster, 1994).