A Tale of Two PMLs: Elements Regulating a Differential Substrate Recognition by the ICP0 E3 Ubiquitin Ligase of Herpes Simplex Virus 1.
Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an α gene product required for viral replication at low multiplicities of infection. Upon entry, nuclear domain 10 (ND10) converges at the incoming DNA and represses viral gene expression. ICP0 contains a RING-type E3 ubiquitin ligase that degrades the ND10 organizer PML and disperses ND10 to alleviate the repression. In the present study, we focused on understanding the regulation of ICP0 E3 ligase activity in the degradation of different ICP0 substrates. We report the following. (i) A SUMO interaction motif located at ICP0 residues 362 to 364 is required for the degradation of PML isoforms II, IV, and VI but not isoform I. This differentiation mechanism exists in both HEp-2 and U2OS cells, regardless of the cell's permissiveness to the ICP0-null virus. (ii) Physical interaction between SIM362-364and PML II is necessary but not sufficient for PML II degradation. Both proximal sequences surrounding SIM362-364and distal sequences located at the ICP0 C terminus enhance the degradation of PML II. (iii) The ICP0 C terminus is dispensable for PML I degradation. Instead, bipartite PML I binding domains located in the N-terminal half of ICP0 coordinate to promote the degradation of PML I. (iv) The stability of ICP0, but not its ND10 fusion ability, affects the rate of PML I degradation. Taken together, our results show that ICP0 uses at least two regulatory mechanisms to differentiate its substrates. The disparate recognition of the ICP0 E3 substrates may be related to the different roles these substrates may play in HSV-1 infection.


OBJECTIVE
Viruses have a limited genetic coding capacity but must encounter a multilayered comprehensive host defense. To establish a successful infection, viruses usually produce multifunctional proteins to coordinate the counteractions. Here we report that an HSV-1 protein, ICP0, can recognize individual host factors and target them differently for destruction. We identified elements that are important for the ICP0 E3 ubiquitin ligase to differentially recognize two of its substrates, PML I and PML II. This is the first study that has systematically investigated how ICP0 discriminates two similar molecules by very different mechanisms. This work lays the foundation for understanding the role of host defensive factors and the mechanisms viruses use to take advantage of some host proteins while destroying others.
Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA.
Yi
Y
Zheng
Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA.
Subodh Kumar
SK
Samrat
Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA haidong.gu@wayne.edu.
Haidong
H
Gu
D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D059748:Proteolysis; D017384:Sequence Deletion; D013379:Substrate Specificity; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
D017874:Immediate-Early Proteins; D050505:Mutant Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014764:Viral Proteins; C070576:PML protein, human; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1
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