RACK1 promotes the development and function of alveolar macrophages through directly binding to and stabilizing PPARγ

Area of Science:

• Immunology
• Cell Biology
• Pulmonary Medicine

Background:

• Alveolar macrophages (AMs) are vital for lung immunity and homeostasis.
• Receptor for activated C kinase 1 (RACK1) is an adaptor protein with diverse signaling roles.
• The function of RACK1 in AMs and its impact on pulmonary health are not well understood.

Purpose of the Study:

• To investigate the role of RACK1 in the development and maintenance of AMs.
• To elucidate the molecular mechanisms by which RACK1 influences AM function.
• To determine the consequences of RACK1 deficiency in AMs on lung immunity.

Main Methods:

• Myeloid-specific RACK1 knockout mouse models.
• Mixed bone marrow chimera experiments.
• Bulk RNA sequencing.
• In vitro differentiation assays with PPARγ agonists.

Main Results:

• Myeloid RACK1 deficiency leads to a scarcity of mature AMs and pulmonary alveolar proteinosis.
• RACK1 is essential for AM differentiation and maintaining AM identity.
• RACK1 directly binds to and stabilizes PPARγ by inhibiting its ubiquitination and degradation.
• RACK1 deficiency impairs PPAR signaling and increases susceptibility to Streptococcus pneumoniae infection.

Conclusions:

• RACK1 plays a critical cell-intrinsic role in AM development and homeostasis.
• RACK1-mediated stabilization of PPARγ is a key mechanism for maintaining AM function.
• RACK1 is essential for host defense against pulmonary bacterial infections.