Abstract
Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB. Accordingly, constitutive processing of p100, caused by the loss of its C-terminal processing inhibitory domain due to nfkappab2 gene rearrangements, is associated with the development of various lymphomas and leukemia. In contrast to the physiological processing of p100 triggered by NF-kappaB-inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha), which requires the E3 ligase, beta-transducin repeat-containing protein (beta-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of beta-TrCP but rather is regulated by the nuclear shuttling of p100. Here, we show that constitutive processing of p100 also requires IKKalpha, but not IKKbeta (IkappaB kinase beta) or IKKgamma (IkappaB kinase gamma). It seems that NIK is also dispensable for this pathogenic processing of p100. These results demonstrate a general role of IKKalpha in p100 processing under both physiological and pathogenic conditions. Additionally, we find that IKKalpha is not required for the nuclear translocation of p100. Thus, these results also indicate that p100 nuclear translocation is not sufficient for the constitutive processing of p100.
Highlights
From the Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854
The IKK␣ Phosphorylation Serines of p100 Are Essential for Its Constitutive Processing— we have demonstrated that IKK␣ is required for p100 processing induced by both NF-Binducing kinase (NIK) and Tax (14, 15), its role in the constitutive processing of p100 remains to be investigated
We have demonstrated that the constitutive processing of p100 is regulated by IKK␣ and it-mediated phosphorylation of p100
Summary
In contrast to the physiological processing of p100 triggered by NF-Binducing kinase (NIK) and its downstream kinase, IB kinase ␣ (IKK␣), which requires the E3 ligase, -transducin repeat-containing protein (-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of -TrCP but rather is regulated by the nuclear shuttling of p100. The canonical NF-B pathway is required for fundamental functions of various cells and can be rapidly and transiently activated by a plethora of substances, such as mitogens, cytokines, and microbial components (11) These stimuli lead to activation of a specific IB kinase (IKK) complex composed of two catalytic subunits, IKK␣ (IKK1) and IKK (IKK2), and a regulatory subunit, IKK␥ (NEMO) (10). The phosphorylation of these specific serines results in ubiquitination and subsequent processing of p100 mediated by the -TrCP ubiquitin ligase and 26S proteasome, respectively (9, 20, 22–24)
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