Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease.
BACKGROUND
Shifts in the gene expression of nuclear protein in chronic obstructive pulmonary disease (COPD), a progressive disease that is characterized by extensive lung inflammation and apoptosis, are common; however, the extent of the elevation of the core histones, which are the major components of nuclear proteins and their consequences in COPD, has not been characterized, which is important because extracellular histones are cytotoxic to endothelial and airway epithelial cells.


OBJECTIVE
To investigate the role of extracellular histones in COPD disease progression.


METHODS
We analyzed the nuclear lung proteomes of ex-smokers with and without the disease. Further studies on the consequences of H3.3 were also performed.


RESULTS
A striking finding was a COPD-specific eightfold increase of hyperacetylated histone H3.3. The hyperacetylation renders H3.3 resistant to proteasomal degradation despite ubiquitination; when combined with the reduction in proteasome activity that is known for COPD, this resistance helps account for the increased levels of H3.3. Using anti-H3 antibodies, we found H3.3 in the airway lumen, alveolar fluid, and plasma of COPD samples. H3.3 was cytotoxic to lung structural cells via a mechanism that involves the perturbation of Ca(2+) homeostasis and mitochondrial toxicity. We used the primary human airway epithelial cells and found that the antibodies to either the C or N terminus of H3 could partially reverse H3.3 toxicity.


CONCLUSIONS
Our data indicate that there is an uncontrolled positive feedback loop in which the damaged cells release acetylated H3.3, which causes more damage, adds H3.3 release, and contributes toward the disease progression.
1 Department of Biochemistry and.
Carlos A
CA
Barrero
Oscar
O
Perez-Leal
Mark
M
Aksoy
Camilo
C
Moncada
Rong
R
Ji
Yolanda
Y
Lopez
Karthik
K
Mallilankaraman
Muniswamy
M
Madesh
Gerard J
GJ
Criner
Steven G
SG
Kelsen
Salim
S
Merali
D000107:Acetylation; D017209:Apoptosis; D018450:Disease Progression; D006657:Histones / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology*
D006657:Histones