A newly published study identifies HERC4 as a protein that marks RIPK1, helping assemble the machinery for two forms of cell death after a tumor-necrosis-factor signal. Mice lacking HERC4 were protected in selected models of severe inflammation and acute liver injury. The results describe a mechanism in cells and mice; no treatment that blocks HERC4 has been tested in people.
Tumor necrosis factor is an immune signal involved in inflammation. The new study identifies a role for the enzyme HERC4 when that signal shifts toward cell death. HERC4 adds a ubiquitin mark to the protein RIPK1, after which death-related proteins assemble. The University of Cologne’s research announcement reports the same HERC4 and RIPK1 finding. The work identifies a step in the movement of the signal between different protein assemblies inside a cell.[1], [2]
RIPK1 participates in an initial protein assembly attached to the cell membrane and associated with survival signaling. Marked RIPK1 molecules then help recruit proteins including FADD and caspase 8 into a death-related assembly. When caspase activity is blocked, another assembly containing RIPK3 can form. These results place HERC4 at a specific step in the formation of two cell-death pathways.[1]
The team exposed mice lacking HERC4 to tumor necrosis factor. Severe systemic inflammation and acute liver injury were reduced in those animals compared with control mice. Alongside the cell experiments, this supports a role for HERC4 under the tested conditions. The researchers did not give a HERC4-blocking drug to people. These experiments do not establish how widely the same mechanism operates across diseases or whether an intervention would be safe for patients.[1]
