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EDITORIALS
Is it NICE (nuclear import as a carcinogenic mechanism) to restrict HBZ in the cytoplasm?
Yukata Tagaya
Institute of Human Virology, University of Maryland School of Medicine, Baltimore MD, USA E-mail: YUKATA TAGAYA - ytagaya@ihv.umaryland.edu
doi:10.3324/haematol.2021.278377
The paper by Forlani et al. found in this volume of Haematologica1 presents an intriguing argument that the control over the subcellular localization of an anti- sense protein (HBZ, HTLV-1 basic-zipper factor) encoded by the human T-cell leukemia virus-1 (HTLV-1) critically con- trols its oncogenicity. HTLV-1 was the first human retrovirus identified2 and is arguably the most carcinogenic agent know to humans.3 Adult T-cell leukemia (ATL)4 is a fatal CD4 type T-cell leukemia that occurs in 5% of HTLV-1 carriers. After 40 years of extensive research since the discovery of HTLV- 1, the precise mechanism by which HTLV-1 transforms host T cells is not completely understood, and the prevailing par- adigm points to two HTLV-1 factors, Tax-1 and HBZ5 as the cause of T-cell leukemia. HBZ is a multi-functional protein and interacts with many cellular proteins. Not only that, HBZ transcripts have their own function as a cancer-promot- ing factor.6 The group led by Roberto Accolla (last author of the paper) has been carefully studying the subcellular distri- bution of HBZ using a monoclonal antibody that they gener- ated, and they observed that HBZ’s localization differs in HTLV-1 infected cells in individuals manifesting different dis- ease status. They found that HBZ exclusively localizes to the cytoplasm7 in cells from asymptomatic carriers and patients with HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), a myelopathy that resembles multiple sclerosis in symptoms and the second major disease manifes- tation that HTLV-1 causes in humans. In contrast, they report in the current article that HBZ localizes in the nucleus in ATL cell lines. Though not exclusive, the nuclear localization of HBZ was distinct in ex vivo leukemic cells from ATL patients. They also showed that the nuclear localization of HBZ may be accompanied by a unidirectional displacement of HBZ from the cytoplasm to the nucleus. With these results, the authors suggest an attractive new hypothesis that the nuclear localization of HBZ is a hallmark of ATL and that the cyto- plasmic-to-nuclear translocation of HBZ plays a major role in the leukemogenic mechanism of HTLV-1. These findings may help establish new diagnosis of ATL as well as provid- ing new insights to the research on HTLV-1’s oncogenesis. So, can a misguided subcellular localization of a particular protein lead to invoking an oncogenic capacity of the pro- tein?
There are a few other examples that could shed light on this question.
Nucleophosmin (NPM) is an example. NPM shuttles between the nucleus and the cytoplasm and the cytoplasmic localization seems to facilitate its tumor promoting activities.8 Another example is STAT3 (signal transducer and activator of transcription-3). STAT3 is a transcription factor involved in the signaling of many cytokines. Gain-of-func- tion mutants of STAT3 are often found in many cancers
including T-cell malignancies. Mutations of STAT3 that are associated with cancer cases cause a self-dimerization of this molecule, which enhances the nuclear transport and binding of STAT3 to the regulatory region of many target genes. In the case of STAT3, the control of subcellular localization per se is not directly connected to the oncogenicity of STAT3, but a mechanism that facilitates the nuclear translocation and DNA binding of STAT3 is likely making STAT3 an oncopro- tein.
So how is the subcellular localization of HBZ controlled? It likely involves the interaction of HBZ with other proteins. Other groups have shown that HBZ can be retained in the cytoplasm by a T cell-specific molecule THEMIS,9 but the Accolla group demonstrated that this does not explain the cytoplasmic distribution of HBZ in HAM/TSP patients.10 Thus, an involvement of another protein for this observation is suggested. Hopefully, future studies will show the clue and help us know how HTLV-1 transforms host CD4 T cells and how we can control the fatal ATL which do not yet have cur- ative treatment.
Disclosures
No clonflicts of interest to disclose.
References
1. Forlani G, Shallak M, Tedeschi A, et al. Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of Adult T cell Leukemia. Haematologica. 2021;106(8):2076-2085.
2.Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cul- tured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980;77(12):7415-7419.
3. Tagaya Y, Gallo RC. The exceptional oncogenicity of HTLV-1. Front Microbiol. 2017;8:1425.
4. Takatsuki K. Adult T-cell leukemia. Intern Med. 1995;34(10):947-952. 5.Satou Y, Yasunaga J, Zhao T, et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog.
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6. Satou Y, Yasunaga J, Yoshida M, Matsuoka M. HTLV-1 bZIP Factor (HBZ)
gene has a growth-promoting effect on adult T-cell leukemia cells].
Rinsho Ketsueki. 2008;49(11):1525-1529.
7.Baratella M, Forlani G, Raval GU, et al. Cytoplasmic localization of
HTLV-1 HBZ protein: a biomarker of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). PLoS Negl Trop Dis. 2017;11(1):e0005285.
8. Lam L, Aktary Z, Bishay M, et al. Regulation of subcellular distribution and oncogenic potential of nucleophosmin by plakoglobin. Oncogenesis. 2012;1:e4.
9. Kinosada H, Yasunaga JI, Shimura K, et al. HTLV-1 bZIP Factor enhances T-Cell proliferation by impeding the suppressive signaling of co-inhibito- ry receptors. PLoS Pathog. 2017;13(1):e1006120.
10. Forlani G, Baratella M, Tedeschi A, Pique C, Jacobson S, Accolla RS. HTLV-1 HBZ protein resides exclusively in the cytoplasm of infected cells in asymptomatic carriers and HAM/TSP patients. Front Microbiol. 2019;10:819.
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