The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.
Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA.
Lawrence R
LR
Shiow
David W
DW
Roadcap
Kenneth
K
Paris
Susan R
SR
Watson
Irina L
IL
Grigorova
Tonya
T
Lebet
Jinping
J
An
Ying
Y
Xu
Craig N
CN
Jenne
Niko
N
Föger
Ricardo U
RU
Sorensen
Christopher C
CC
Goodnow
James E
JE
Bear
Jennifer M
JM
Puck
Jason G
JG
Cyster
D051376:Actin-Related Protein 2-3 Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D048430:Cell Shape; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D008840:Microfilament Proteins; C072061:coronin proteins; D018698:Glutamic Acid; D008239:Lysine