Selected publications

• Townsend Alain and Drakesmith Hal (2002) Role of HFE in iron metabolism, hereditary haemochromatosis, anaemia of chronic disease, and secondary iron overload. Lancet, 359(9308):786-90.

• Drakesmith Hal, Schimanski Lisa M, Ormerod Emma, Merryweather-Clarke Alison T, Viprakasit Vip, Edwards Jon P, Sweetland Emma, Bastin Judy M, Cowley Diana, Chinthammitr Yingyong, Robson Kathryn JH, and Townsend Alain RM (2005) Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood, 106(3):1092-7.

• Drakesmith Hal, Sweetland Emma, Schimanski Lisa, Edwards Jon, Cowley Diana, Ashraf Mubeen, Bastin Judy, and Townsend Alain RM (2002) The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci U S A, 99(24):15602-7.

• Bastin Judy, Drakesmith Hal, Rees Margaret, Sargent Ian, and Townsend Alain (2006) Localisation of proteins of iron metabolism in the human placenta and liver. Br J Haematol, 134(5):532-43.

• Schimanski Lisa M, Drakesmith Hal, Talbott Charlotte, Horne Kerry, James John R, Davis Simon J, Sweetland Emma, Bastin Judy, Cowley Diana, and Townsend Alain RM (2008) Ferroportin: lack of evidence for multimers. Blood Cells Mol Dis, 40(3):360-9.

Prof Alain Townsend

The two proteins we are focussing on are HFE and ferroportin. HFE is mutated in the most common single-gene disorder in Caucasians, hereditary haemochromatosis. Patients with haemochromatosis continually absorb excess iron from the diet. This iron deposits in the liver, heart and pancreas, leading to organ damage and eventually to death. HFE protein is structurally similar to Major Histocompatibility Complex Class I molecules (figure 1), a type of protein with which the lab has a long-standing interest.

Figure 1: Structural similarity between HLA-A2 (left) and HFE (right)

 MHC Class I proteins regulate immune responses, interacting with T lymphocytes and Natural Killer cells. However the precise function of HFE in iron metabolism and/or immunity remains enigmatic (ref 7). In our studies, we found that HFE can inhibit iron import and iron export from cells (ref 6). We have also defined the tissue distribution of HFE (ref 2, and figure 2), identified three new HFE ligands.

Figure 2: HFE expression  on Kupffer cells

Ferroportin is a transporter protein that mediates iron efflux from macrophages and is inhibited by hepcidin. Mutant forms of ferroportin are associated with dominantly inherited iron overload. We showed that ferroportin mutants cause either loss of function or resistance to hepcidin (refs 4,5). We continue to explore ferroportin/hepcidin interactions, in order to understand the disease inheritance pattern (ref 1).

In HIV/AIDS, progressive iron loading of macrophages is inversely correlated with survival. We found one component of HIV-1, the Nef protein, interferes with HFE trafficking and function (figure 3); in macrophages this leads to iron accumulation and enhanced viral replication (ref 3). Preliminary experiments indicate macrophages from haemochromatosis patients (expressing mutated HFE) withstand this mechanism. The nature of the interaction between iron and HIV-1 is being explored with the aim being to limit viral growth.

Figure 3: HFE (red in cell on left) is rerouted by HIV-1 Nef (green, right). HFE colocalizes with Nef (yellow) in the golgi body.