Glycoproteins M and N (gM and gN, respectively) are among the few proteins that are conserved across the herpesvirus family. The function of the complex is largely unknown. Whereas deletion from most alphaherpesviruses has marginal effects on the replication of the respective viruses, both proteins are essential for replication of human cytomegalovirus (HCMV). We have constructed a series of mutants in gN to study the function of this protein. gN of HCMV is a type I glycoprotein containing a short carboxy-terminal domain of 14 amino acids, including two cysteine residues directly adjacent to the predicted transmembrane anchor at positions 125 and 126. Deletion of the entire carboxy-terminal domain as well as substitution with the corresponding region from alpha herpesviruses or mutations of both cysteine residues resulted in a replicationincompetent virus. Recombinant viruses containing point mutations of either cysteine residue could be generated. These viruses were profoundly defective for replication. Complex formation of the mutant gNs with gM and transport of the complex to the viral assembly compartment appeared unaltered compared to the wild type. However, in infected cells, large numbers of capsids accumulated in the cytoplasm that failed to acquire an envelope. Transiently expressed gN was shown to be modified by palmitic acid at both cysteine residues. In summary, our data suggest that the carboxy-terminal domain of gN plays a critical role in secondary envelopment of HCMV and that palmitoylation of gN appears to be essential for function in secondary envelopment of HCMV and virus replication.The formation of an infectious herpesvirus is exceedingly complex and requires the assembly of an enveloped particle containing Ͼ70 proteins. The morphogenesis of this particle is still not understood. A currently widely accepted view suggests that two separate envelopment stages occur within the infected host cell and have led to the proposed envelopment-de-envelopment-reenvelopment model (36). According to this model, a primary envelopment occurs when capsids bud at the inner nuclear membrane to become enveloped particles in the perinuclear space. These particles subsequently fuse with the outer nuclear membrane, leading to the release of capsids into the cytoplasm. The secondary envelopment occurs when capsids which have accumulated tegument proteins in the cytoplasm bud into the lumen of a compartment that carries markers of the late secretory pathway and the trans-Golgi network (TGN), operationally defined as the assembly compartment (49). It is here where herpesviruses acquire their complete set of envelope glycoproteins. It should be noted that this model is not universally accepted (31). In any case, the successful envelopment of the tegumented capsid requires that all envelope components be concentrated in the assembly compartment, a process that in itself also likely demands a high degree of structural and temporal coordination.Glycoproteins M and N (gM and gN, respectively) are among the few envelope gl...
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