title: A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals.
abstract: More than 60 members of the Rab family of guanosine triphosphatases (GTPases) exist in the human genome. Rab GTPases are small proteins that are primarily involved in the formation, trafficking, and fusion of vesicles. We showed thatCRACR2A(Ca(2+) release-activated Ca(2+) channel regulator 2A) encodes a lymphocyte-specific large Rab GTPase that contains multiple functional domains, including EF-hand motifs, a proline-rich domain (PRD), and a Rab GTPase domain with an unconventional prenylation site. Through experiments involving gene silencing in cells and knockout mice, we demonstrated a role for CRACR2A in the activation of the Ca(2+) and c-Jun N-terminal kinase signaling pathways in response to T cell receptor (TCR) stimulation. Vesicles containing this Rab GTPase translocated from near the Golgi to the immunological synapse formed between a T cell and a cognate antigen-presenting cell to activate these signaling pathways. The interaction between the PRD of CRACR2A and the guanidine nucleotide exchange factor Vav1 was required for the accumulation of these vesicles at the immunological synapse. Furthermore, we demonstrated that GTP binding and prenylation of CRACR2A were associated with its localization near the Golgi and its stability. Our findings reveal a previously uncharacterized function of a large Rab GTPase and vesicles near the Golgi in TCR signaling. Other GTPases with similar domain architectures may have similar functions in T cells.
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. ygwack@mednet.ucla.edu ssrikanth@mednet.ucla.edu.
authors.forename: Sonal
authors.initials: S
authors.lastname: Srikanth
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Kyun-Do
authors.initials: KD
authors.lastname: Kim
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Woo
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Shubhamoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Calmettes
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Paz
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Abramson
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Meisheng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. ygwack@mednet.ucla.edu ssrikanth@mednet.ucla.edu.
authors.forename: Yousang
authors.initials: Y
authors.lastname: Gwack
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054992:Immunological Synapses / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: C551025:CRACR2A protein, human; D002135:Calcium-Binding Proteins