The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow

Abstract

B lymphopoiesis begins in fetal liver, switching to bone marrow after birth where it persists for life. The unique developmental outcomes of each phase are well documented, yet their molecular requirements are not. Here we describe two allelic X-linked mutations in mice that caused a cell-intrinsic arrest of adult B lymphopoiesis. Mutant fetal liver progenitors generated B cells in situ, but not in irradiated adult bone marrow, highlighting a necessity for the affected pathway only in the context of adult bone marrow. The causative mutation was ascribed to Atp11c, which encodes a P4-type ATPase with no previously described function. Our data establish an essential, cell-autonomous and context-sensitive function for ATP11C, a putative aminophospholipid flippase, in B cell development.

Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection

“…The daniel gray strain is available from the Mutant Mouse Regional Resource Center (034372-JAX). The Rag1 maladaptive strain (Rag1 m1Btlr ; Mouse Genome Informatics ID 3851764) was developed inhouse (27), whereas Tg(BCL2)25Wehi (28) Linkage Analysis. The index daniel gray mutant (C57BL/6J) was outcrossed to C3H/HeN females, and F 1 daughters were backcrossed to their father.…”

Exposure of phosphatidylserine on the cell surface

“…On the other hand, and ATP11C-null mice suffer from B-cell lymphopenia, cholestasis, anemia, dystocia and hepatocellular carcinoma. [86][87][88][89] In ATP11C-null B cells and erythrocytes, the flippase activity is reduced and the population of erythrocytes that expose PtdSer is slightly increased. 88,89 How this small effect on flippase activity in ATP11C − / − cells leads to the strong phenotypes seen in ATP11C-null mice is unclear.…”

ATP11C mutation is responsible for the defect in phosphatidylserine uptake in UPS-1 cells

“…It is likely that ATP11C is a major P4-ATPase involved in PS fl ipping in CHO cells. ATP11C-defi cient mice exhibit anemia, hyperbilirubinemia, abnormal differentiation of B cells, and hepatocellular carcinoma ( 17,18,29 ). Hopefully, UPS-1 cells will be useful for understanding the physiological and pathophysiological roles of ATP11C.…”